Review Article Roles of Osteopontin Gene Polymorphism...

10
Review Article Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels in Urine and Serum, and the Risk of Urolithiasis: A Meta-Analysis Xiao Li, Kang Liu, Yongsheng Pan, Jing Zhang, Qiang Lv, Lixin Hua, Zengjun Wang, Jie Li, and Changjun Yin Department of Urology, e First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Correspondence should be addressed to Jie Li; lijie [email protected] and Changjun Yin; ycj [email protected] Received 7 November 2014; Revised 16 January 2015; Accepted 17 January 2015 Academic Editor: Roberto Cirocchi Copyright © 2015 Xiao Li et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Previous studies have investigated the relationships between osteopontin gene polymorphism rs1126616 and OPN levels and urolithiasis, but the results were controversial. Our study aimed to clarify such relationships. Methods. A meta-analysis was performed by searching the databases Pubmed, Embase, and Web of Science for relevant studies. Crude odds ratios (ORs) or standardised mean differences with 95% confidence intervals (CIs) were calculated to evaluate the strength of association. Publication bias was estimated using Begg’s funnel plots and Egger’s regression test. Results. Overall, a significantly increased risk of urolithiasis was associated with OPN gene polymorphism rs1126616 for all the genetic models except recessive model. When stratified by ethnicity, the results were significant only in Turkish populations. For OPN level association, a low OPN level was detected in the urine of urolithiasis patients in large sample size subgroup. Results also indicated that urolithiasis patients have lower OPN level in serum than normal controls. Conclusion. is meta-analysis revealed that the T allele of OPN gene polymorphism increased susceptibility to urolithiasis. Moreover, significantly lower OPN levels were detected in urine and serum of urolithiasis patients than normal controls, thereby indicating that OPN has important functions in the progression of urolithiasis. 1. Introduction Urolithiasis is one of the most common diseases that affect all ethnicities and populations worldwide. Urinary stone forma- tion is a complicated disorder involved in a process of nucle- ation, growth, aggregation, and retention of crystals in the urine [1, 2]. Among all types of urinary stones, calcium, stru- vite, uric acid, and cystine stones account for 70% to 80%, 5% to 10%, 5% to 10%, and 1%, respectively [3]. In recent years, despite considerable efforts by researchers, the lithogenic and inhibitory pathogenic mechanisms of urolithiasis remain unknown. Urolithiasis is associated with acidic macromolecules, which direct nucleation, growth, and morphology by both molecular templating and preferential adsorption onto spe- cific crystal faces [4, 5]. Osteopontin (OPN) is a unique acidic macromolecule with the crucial biological function of inhibiting urinary crystallization by possibly reducing the growth and aggregation of calcium oxalate (CaO X ) crystals and inhibiting the binding of CaO X crystals directly to renal tubular epithelial cells [6, 7]. Nonetheless, osteopontin is presumably one of the most important components in the cal- cium stone matrix, implying its potential role in urolithiasis. As a multifactorial disease, urolithiasis is associated with the effects of multiple genes combined with lifestyle and envi- ronmental influences [8]. Familial clustering of idiopathic urolithiasis has been confirmed by a growing number of epi- demiologic studies, suggesting that genetic factors play a sig- nificant role in urinary stone formation [9]. Osteopontin is a 44 kDa negatively charged acidic hydrophilic multifunctional protein that contains a functional Gly-Arg-Gly-Asp-Ser cell- binding sequence and encoded by the OPN gene, which is located on chromosome 4q21-25 and spans approximately 11 kb with 7 exons [1013]. e single nucleotide polymor- phism rs11226616 of OPN gene means +750 C > T in exon VII of 3 UTR, which can also be expressed by OPN C6982T Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 315043, 9 pages http://dx.doi.org/10.1155/2015/315043

Transcript of Review Article Roles of Osteopontin Gene Polymorphism...

Page 1: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

Review ArticleRoles of Osteopontin Gene Polymorphism (rs1126616)Osteopontin Levels in Urine and Serum and the Risk ofUrolithiasis A Meta-Analysis

Xiao Li Kang Liu Yongsheng Pan Jing Zhang Qiang LvLixin Hua Zengjun Wang Jie Li and Changjun Yin

Department of Urology The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 China

Correspondence should be addressed to Jie Li lijie urology163com and Changjun Yin ycj urology163com

Received 7 November 2014 Revised 16 January 2015 Accepted 17 January 2015

Academic Editor Roberto Cirocchi

Copyright copy 2015 Xiao Li et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Objective Previous studies have investigated the relationships between osteopontin gene polymorphism rs1126616 and OPN levelsand urolithiasis but the results were controversial Our study aimed to clarify such relationships Methods A meta-analysiswas performed by searching the databases Pubmed Embase and Web of Science for relevant studies Crude odds ratios (ORs)or standardised mean differences with 95 confidence intervals (CIs) were calculated to evaluate the strength of associationPublication bias was estimated using Beggrsquos funnel plots and Eggerrsquos regression test Results Overall a significantly increased riskof urolithiasis was associated with OPN gene polymorphism rs1126616 for all the genetic models except recessive model Whenstratified by ethnicity the results were significant only in Turkish populations For OPN level association a low OPN level wasdetected in the urine of urolithiasis patients in large sample size subgroup Results also indicated that urolithiasis patients have lowerOPN level in serum than normal controls Conclusion This meta-analysis revealed that the T allele of OPN gene polymorphismincreased susceptibility to urolithiasis Moreover significantly lower OPN levels were detected in urine and serum of urolithiasispatients than normal controls thereby indicating that OPN has important functions in the progression of urolithiasis

1 Introduction

Urolithiasis is one of themost common diseases that affect allethnicities and populations worldwide Urinary stone forma-tion is a complicated disorder involved in a process of nucle-ation growth aggregation and retention of crystals in theurine [1 2] Among all types of urinary stones calcium stru-vite uric acid and cystine stones account for 70 to 80 5to 10 5 to 10 and 1 respectively [3] In recent yearsdespite considerable efforts by researchers the lithogenicand inhibitory pathogenicmechanisms of urolithiasis remainunknown

Urolithiasis is associated with acidic macromoleculeswhich direct nucleation growth and morphology by bothmolecular templating and preferential adsorption onto spe-cific crystal faces [4 5] Osteopontin (OPN) is a unique acidicmacromolecule with the crucial biological function ofinhibiting urinary crystallization by possibly reducing the

growth and aggregation of calcium oxalate (CaOX) crystalsand inhibiting the binding of CaOX crystals directly to renaltubular epithelial cells [6 7] Nonetheless osteopontin ispresumably one of themost important components in the cal-cium stone matrix implying its potential role in urolithiasis

As a multifactorial disease urolithiasis is associated withthe effects ofmultiple genes combinedwith lifestyle and envi-ronmental influences [8] Familial clustering of idiopathicurolithiasis has been confirmed by a growing number of epi-demiologic studies suggesting that genetic factors play a sig-nificant role in urinary stone formation [9] Osteopontin is a44 kDa negatively charged acidic hydrophilicmultifunctionalprotein that contains a functional Gly-Arg-Gly-Asp-Ser cell-binding sequence and encoded by the OPN gene which islocated on chromosome 4q21-25 and spans approximately11 kb with 7 exons [10ndash13] The single nucleotide polymor-phism rs11226616 of OPN gene means +750 C gt T in exonVII of 31015840 UTR which can also be expressed by OPN C6982T

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 315043 9 pageshttpdxdoiorg1011552015315043

2 BioMed Research International

Table 1 Characteristics of studies included in the meta-analysis for association between OPN C6982T polymorphism and urolithiasis

OPN rs1126616 Case (119873) Control (119873)Year Author Ethnicity Genotyping SOC Case Control CC1 CT1 TT1 CC0 CT0 TT02013 Tugcu et al [25] Turkish PCR-RFLP PB 127 92 66 42 19 70 8 142013 Safarinejad et al [26] Asian PCR-RFLP PB 342 684 27 143 172 41 315 3282012 Tekin et al [27] Turkish PCR-RFLP PB 64 50 27 27 10 33 13 42010 Gogebakan et al [28] Turkish PCR-SSCP PB 121 100 23 67 31 32 61 72000 Yamate et al [14] Asian PCR-SSCP PB 65 36 2 39 24 11 16 9SOC source of controls PB population-based study

polymorphism Genetic variations of the OPN gene havebeen described and some of these variations were reportedlyassociated with calcium in patients with urolithiasis [14ndash16]showing that rs1126616 can potentially explain urolithiasissusceptibility However whether rs1126616 of OPN gene caninfluence urolithiasis remains unclear

Though previous studies showed the associations bet-ween OPN gene polymorphism (rs1126616) and OPN levelswith urolithiasis the information in each of the publishedstudies was limited and the results were inconsistent or evencontradictory Thus we performed a meta-analysis of alleligible studies to provide a more accurate estimate of theassociation of the OPN gene polymorphisms and the risk ofurolithiasis Additionally the differences in urine and serumOPN levels between patients with urolithiasis and the controlsubjects were also compared

2 Materials and Methods

We conducted a comprehensive search of PubMed Embaseand Web of Science for relevant studies on the associationbetween OPN gene polymorphism (rs1126616) and OPNlevels with urolithiasis Our search covered all the paperspublished up to 30 September 2014 The combinations of thefollowing keywords were used ldquoOsteopontinrdquo or ldquoOPNrdquoldquopolymorphismrdquo or ldquolevelrdquo and ldquoUrolithiasisrdquo or ldquoUrinary cal-culirdquo or ldquoUrinary stonerdquo We collected additional literature bymanual searching of the references of original studies orreviews Only the latest or most comprehensive sample sizewas included if studies had partly overlapping subjects If thesame case series were used in more than one article only thestudy with the largest sample size was selected

Studies involved were selected if they met the inclusioncriteria as follows (1) case-control design was used (2) forgenotype frequency association the number of each genotypemust be clear and sufficient data must be provided for calcu-lating the odds ratio (OR) and the corresponding 95 confi-dence interval (CI) (3) for OPN levels association the studymust have clear original data on the OPN levels in urine orserum The major exclusion criterion was duplicates ofprevious publication

21 Data Extraction Two investigators (Xiao Li andKangLiu)independently and carefully reviewed the identified studies todetermine whether an individual study was eligible for inclu-sion The investigators independently extracted data from

studies involved and disagreements were resolved by dis-cussion The following data were collected from each studyfirst authorrsquos name year of publication ethnicity genotypingmethod source of controls number of cases and controlsfrequency of rs1126616 gene polymorphism in cases andcontrols the mean of OPN levels and SD All data wererecorded in a standardised form

22 Statistical Analysis The pooled ORs or standardisedmean differences (SMD) with 95 CI were used to respec-tively evaluate the strength of association between thers1126616 genotype and OPN levels with urolithiasis suscep-tibilityWe used SMD because the OPN levels were measuredby different methods in the included studies A 95 CI with-out 1 for OR indicated a significantly increased or reducedurolithiasis risk The fixed-effects model (Mantel-Haenszelmethod) and the random effects model (DerSimonian-Lairdmethod) were used to pool the data [17] Sensitivity analysisinvolved calculating the results again by omitting one singlestudy each time Metaregression analysis was performed toexplore the sources of heterogeneity if significant heterogene-ity was present among studies Subgroup analysis was per-formed by ethnicity and genotyping methods Beggrsquos funnelplots and Eggerrsquos linear regression test were used to examinethe publication bias between the studies and a 119875 lt 005was considered significant [18] Hardy-Weinberg equilibrium(HWE) was evaluated using the goodness-of-fit chi-squaretest and 119875 lt 005 was regarded a significantly selective bias[19]

All statistical analyses were performedwith Stata software(version 120 StataCorp LP College Station TX) 119875 valueswere all two-sided and were considered statistically signifi-cant when being less than 005

3 Results

31 Studies Characteristics A total of 11 case-control studieswere involved in the meta-analysis [14 16 20ndash28] and thedetails of the studies containing data on OPN gene poly-morphism (rs1126616) and OPN levels in serum or urineare shown in Tables 1 and 2 respectively Figure 1 shows theflowchart of the literature search and selection process All thesource of controls was the healthy population DNA wasextracted from whole blood in all these studies and twogenotyping methods were used namely polymerase chainreaction- (PCR-) restriction fragment length polymorphism

BioMed Research International 3

Table 2 Characteristics of individual studies included in the meta-analysis of OPN level and urolithiasis

OPN level in urineYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 0028 0021 684 0048 00272012 Salama et al [24] Asian Saudi Arabia 25 15 2167 37 10 5888 172012 Kolbach et al [23] Caucasian USA 26 13 25 15 13 40 22010 Liu et al [16] Asian China 496 249 0029 0024 247 0050 00312003 Huang et al [20] Asian China 64 32 1018 131 32 559 1081999 Yasui et al [21] Asian Japan 60 47 3577 2792 13 8879 35281996 Bautista et al [22] Caucasian England 57 34 076 071 23 079 076

OPN level in serumYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 42 16 684 64 162013 Tugcu et al [25] Caucasian Turkey 219 127 45 28 92 83 372012 Salama et al [24] Asian Saudi Arabia 25 15 1120 230 10 2025 380

Articles searched by

For urolithiasis OPN level

(n = 28)

(n = 10)(n = 5)

(n = 4)

(n = 8)

(n = 5)

(n = 7)

For

Citations identified and screened

Not case-control study(n = 8)Not related to Rs1126616

Review

Eligible articles

hand

Figure 1 Flow diagram of literature search and selection process

(RFLP) and PCR-single-strand conformation polymorphism(SSCP) Urolithiasis was confirmed by ultrasonography orradiography in all studies

32 Meta-Analysis Results The main results of the meta-analysis of the association between OPN gene polymorphismrs1126616 and urolithiasis are listed in Table 3 Overall thepooled OR was 249 (95 CI 101ndash617) for heterozygotemodel 271 (95 CI 102ndash715) for homozygote model 231(95 CI 110ndash485) for dominant model and 164 (95 CI095ndash281) for recessive model (Figure 2) When the studieswere stratified by ethnicity the results were positive only inTurkish populations (heterozygote model pooled OR = 26995 CI 126ndash575 homozygote model pooled OR = 28895 CI 114ndash730 dominant model pooled OR = 250 95CI 172ndash363 Figure 3(a)) Moreover when the studies werestratified by genotyping method the result was significantonly in the PCR-SSCPmethod with a pooledORof 766 (95CI 328ndash1789) for the homozygote model and 286 (95 CI112ndash733) for the recessive model (Figure 3(b))

For the association of OPN level the detailed results areshown inTable 4Thepooled SMDwasminus055 (95CIminus130ndash020) for the association between OPN levels in urine and

urolithiasis risk (Figure 4(a))When the studies onOPN levelin urine were stratified by ethnicity the results were negativein both the Asian and Turkish subgroups with a pooled SMDof minus149 (95 CI minus379ndash081) and minus055 (95 CI minus130ndash020) However the results were positive when the studieswere stratified by sample size and a lowOPN level was foundin urine of urolithiasis patients in large sample size subgroupFurthermore our results indicated that reduced OPN levelwas evident in the serum of urolithiasis patients comparedwith normal controls (SMD = minus147 95 CI minus189 to minus104Figure 4(b))

33 Test of Heterogeneity For OPN gene polymorphismrs1126616 association a significant heterogeneity wasobserved in all the genetic models However heterogeneitydecreased when subgroup analyses were conducted by eth-nicity or by using genotyping methods For the OPN levelsassociation in urine or serum heterogeneity between studieswas also observed in overall comparisons as well as in sub-group analyses However heterogeneity was also reduced bysubgroup analyses We failed to confirm the source of theheterogeneity because of overmuch confounding factors

4 BioMed Research International

Table 3 Meta-analysis results of the association between OPN C6982T polymorphism and urolithiasis risk

119873a Sample size CT versus CC 119875b TT versus CC 119875b CTTT versus CC 119875b TT versus CTCC 119875b

Total 5 1681 249 (101ndash617) 0000 271 (102ndash715) 0000 231 (110ndash485) 0000 164 (095ndash281) 0024Ethnicity

Asian 2 1127 275 (015ndash5189) 0001 305 (017ndash5374) 0001 291 (016ndash5275) 0000 114 (089ndash146) 0329Turkish 3 554 269 (126ndash575) 0052 288 (114ndash730) 0070 250 (172ndash363) 0669 208 (076ndash567) 0030

GenotypingPCR-RFLP 3 1359 207 (056ndash767) 0000 128 (064ndash254) 0108 176 (068ndash457) 0001 111 (088ndash142) 0549PCR-SSCP 2 322 397 (047ndash3324) 0014 766 (328ndash1789) 0384 458 (070ndash3018) 0024 286 (112ndash733) 0134aNumber of studiesb119875 value of119876 test for heterogeneity

Note weights are from random effects analysis

Study ID

271 (102 715)

144 (067 310)

306 (086 1084)

080 (047 134)

OR (95 CI)

616 (231 1641)

1467 (271 7950)

10000

2243

1808

2427

Weight ()

2062

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

Study ID

231 (110 485)

266 (124 573)

294 (163 532)

074 (045 123)

OR (95 CI)

1386 (287 6704)

201 (108 372)

10000

2037

2235

2327

Weight ()

1194

2206

00149 1 67

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(b)

Figure 2 Forest plots of urolithiasis associated with distribution of genotypic frequencies of rs1126616 (a) Homozygote model (b) dominantmodel

BioMed Research International 5

Table 4 Summary of SMD and 95 CI for associations between OPN level and urolithiasis risk

Polymorphism Subgroup 119873a Sample size SMD (95 CI) 119875 value 119875 heterogeneity

UrineAll 7 1754 minus055 (minus130ndash020) 0151 lt00001

Large sample size 2 1522 minus078 (minus089 to minus067) lt00001 0749Asian populations 5 1671 minus065 (minus161ndash031) 0182 lt00001

Serum All 3 1270 minus147 (minus189 to minus104) lt00001 001aThe number of studies

Note weights are from random effects analysis

Study ID

2

1

271 (102 715)

144 (067 310)

306 (086 1084)

616 (231 1641)

080 (047 134)

288 (114 730)

OR (95 CI)

305 (017 5374)

1467 (271 7950)

10000

2243

1808

2062

2427

6114

Weight ()

3886

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 906 P = 0001)

Subtotal (I2 = 624 P = 0070)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

2

Study ID

1

271 (102 715)

766 (328 1789)

128 (064 254)

080 (047 134)

616 (231 1641)

1467 (271 7950)

144 (067 310)

306 (086 1084)

OR (95 CI)

10000

3521

6479

2427

2062

1459

2243

1808

Weight ()

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 551 P = 0108)

Subtotal (I2 = 00 P = 0384)

Yamate et al 2000

oG 2010gebakan et al

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

(b)

Figure 3 Forest plots of subgroup analysis of urolithiasis associated with the distribution of genotypic frequencies of rs1126616 in thehomozygote model (a) stratified by ethnicity (b) stratified by genotyping method

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 2: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

2 BioMed Research International

Table 1 Characteristics of studies included in the meta-analysis for association between OPN C6982T polymorphism and urolithiasis

OPN rs1126616 Case (119873) Control (119873)Year Author Ethnicity Genotyping SOC Case Control CC1 CT1 TT1 CC0 CT0 TT02013 Tugcu et al [25] Turkish PCR-RFLP PB 127 92 66 42 19 70 8 142013 Safarinejad et al [26] Asian PCR-RFLP PB 342 684 27 143 172 41 315 3282012 Tekin et al [27] Turkish PCR-RFLP PB 64 50 27 27 10 33 13 42010 Gogebakan et al [28] Turkish PCR-SSCP PB 121 100 23 67 31 32 61 72000 Yamate et al [14] Asian PCR-SSCP PB 65 36 2 39 24 11 16 9SOC source of controls PB population-based study

polymorphism Genetic variations of the OPN gene havebeen described and some of these variations were reportedlyassociated with calcium in patients with urolithiasis [14ndash16]showing that rs1126616 can potentially explain urolithiasissusceptibility However whether rs1126616 of OPN gene caninfluence urolithiasis remains unclear

Though previous studies showed the associations bet-ween OPN gene polymorphism (rs1126616) and OPN levelswith urolithiasis the information in each of the publishedstudies was limited and the results were inconsistent or evencontradictory Thus we performed a meta-analysis of alleligible studies to provide a more accurate estimate of theassociation of the OPN gene polymorphisms and the risk ofurolithiasis Additionally the differences in urine and serumOPN levels between patients with urolithiasis and the controlsubjects were also compared

2 Materials and Methods

We conducted a comprehensive search of PubMed Embaseand Web of Science for relevant studies on the associationbetween OPN gene polymorphism (rs1126616) and OPNlevels with urolithiasis Our search covered all the paperspublished up to 30 September 2014 The combinations of thefollowing keywords were used ldquoOsteopontinrdquo or ldquoOPNrdquoldquopolymorphismrdquo or ldquolevelrdquo and ldquoUrolithiasisrdquo or ldquoUrinary cal-culirdquo or ldquoUrinary stonerdquo We collected additional literature bymanual searching of the references of original studies orreviews Only the latest or most comprehensive sample sizewas included if studies had partly overlapping subjects If thesame case series were used in more than one article only thestudy with the largest sample size was selected

Studies involved were selected if they met the inclusioncriteria as follows (1) case-control design was used (2) forgenotype frequency association the number of each genotypemust be clear and sufficient data must be provided for calcu-lating the odds ratio (OR) and the corresponding 95 confi-dence interval (CI) (3) for OPN levels association the studymust have clear original data on the OPN levels in urine orserum The major exclusion criterion was duplicates ofprevious publication

21 Data Extraction Two investigators (Xiao Li andKangLiu)independently and carefully reviewed the identified studies todetermine whether an individual study was eligible for inclu-sion The investigators independently extracted data from

studies involved and disagreements were resolved by dis-cussion The following data were collected from each studyfirst authorrsquos name year of publication ethnicity genotypingmethod source of controls number of cases and controlsfrequency of rs1126616 gene polymorphism in cases andcontrols the mean of OPN levels and SD All data wererecorded in a standardised form

22 Statistical Analysis The pooled ORs or standardisedmean differences (SMD) with 95 CI were used to respec-tively evaluate the strength of association between thers1126616 genotype and OPN levels with urolithiasis suscep-tibilityWe used SMD because the OPN levels were measuredby different methods in the included studies A 95 CI with-out 1 for OR indicated a significantly increased or reducedurolithiasis risk The fixed-effects model (Mantel-Haenszelmethod) and the random effects model (DerSimonian-Lairdmethod) were used to pool the data [17] Sensitivity analysisinvolved calculating the results again by omitting one singlestudy each time Metaregression analysis was performed toexplore the sources of heterogeneity if significant heterogene-ity was present among studies Subgroup analysis was per-formed by ethnicity and genotyping methods Beggrsquos funnelplots and Eggerrsquos linear regression test were used to examinethe publication bias between the studies and a 119875 lt 005was considered significant [18] Hardy-Weinberg equilibrium(HWE) was evaluated using the goodness-of-fit chi-squaretest and 119875 lt 005 was regarded a significantly selective bias[19]

All statistical analyses were performedwith Stata software(version 120 StataCorp LP College Station TX) 119875 valueswere all two-sided and were considered statistically signifi-cant when being less than 005

3 Results

31 Studies Characteristics A total of 11 case-control studieswere involved in the meta-analysis [14 16 20ndash28] and thedetails of the studies containing data on OPN gene poly-morphism (rs1126616) and OPN levels in serum or urineare shown in Tables 1 and 2 respectively Figure 1 shows theflowchart of the literature search and selection process All thesource of controls was the healthy population DNA wasextracted from whole blood in all these studies and twogenotyping methods were used namely polymerase chainreaction- (PCR-) restriction fragment length polymorphism

BioMed Research International 3

Table 2 Characteristics of individual studies included in the meta-analysis of OPN level and urolithiasis

OPN level in urineYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 0028 0021 684 0048 00272012 Salama et al [24] Asian Saudi Arabia 25 15 2167 37 10 5888 172012 Kolbach et al [23] Caucasian USA 26 13 25 15 13 40 22010 Liu et al [16] Asian China 496 249 0029 0024 247 0050 00312003 Huang et al [20] Asian China 64 32 1018 131 32 559 1081999 Yasui et al [21] Asian Japan 60 47 3577 2792 13 8879 35281996 Bautista et al [22] Caucasian England 57 34 076 071 23 079 076

OPN level in serumYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 42 16 684 64 162013 Tugcu et al [25] Caucasian Turkey 219 127 45 28 92 83 372012 Salama et al [24] Asian Saudi Arabia 25 15 1120 230 10 2025 380

Articles searched by

For urolithiasis OPN level

(n = 28)

(n = 10)(n = 5)

(n = 4)

(n = 8)

(n = 5)

(n = 7)

For

Citations identified and screened

Not case-control study(n = 8)Not related to Rs1126616

Review

Eligible articles

hand

Figure 1 Flow diagram of literature search and selection process

(RFLP) and PCR-single-strand conformation polymorphism(SSCP) Urolithiasis was confirmed by ultrasonography orradiography in all studies

32 Meta-Analysis Results The main results of the meta-analysis of the association between OPN gene polymorphismrs1126616 and urolithiasis are listed in Table 3 Overall thepooled OR was 249 (95 CI 101ndash617) for heterozygotemodel 271 (95 CI 102ndash715) for homozygote model 231(95 CI 110ndash485) for dominant model and 164 (95 CI095ndash281) for recessive model (Figure 2) When the studieswere stratified by ethnicity the results were positive only inTurkish populations (heterozygote model pooled OR = 26995 CI 126ndash575 homozygote model pooled OR = 28895 CI 114ndash730 dominant model pooled OR = 250 95CI 172ndash363 Figure 3(a)) Moreover when the studies werestratified by genotyping method the result was significantonly in the PCR-SSCPmethod with a pooledORof 766 (95CI 328ndash1789) for the homozygote model and 286 (95 CI112ndash733) for the recessive model (Figure 3(b))

For the association of OPN level the detailed results areshown inTable 4Thepooled SMDwasminus055 (95CIminus130ndash020) for the association between OPN levels in urine and

urolithiasis risk (Figure 4(a))When the studies onOPN levelin urine were stratified by ethnicity the results were negativein both the Asian and Turkish subgroups with a pooled SMDof minus149 (95 CI minus379ndash081) and minus055 (95 CI minus130ndash020) However the results were positive when the studieswere stratified by sample size and a lowOPN level was foundin urine of urolithiasis patients in large sample size subgroupFurthermore our results indicated that reduced OPN levelwas evident in the serum of urolithiasis patients comparedwith normal controls (SMD = minus147 95 CI minus189 to minus104Figure 4(b))

33 Test of Heterogeneity For OPN gene polymorphismrs1126616 association a significant heterogeneity wasobserved in all the genetic models However heterogeneitydecreased when subgroup analyses were conducted by eth-nicity or by using genotyping methods For the OPN levelsassociation in urine or serum heterogeneity between studieswas also observed in overall comparisons as well as in sub-group analyses However heterogeneity was also reduced bysubgroup analyses We failed to confirm the source of theheterogeneity because of overmuch confounding factors

4 BioMed Research International

Table 3 Meta-analysis results of the association between OPN C6982T polymorphism and urolithiasis risk

119873a Sample size CT versus CC 119875b TT versus CC 119875b CTTT versus CC 119875b TT versus CTCC 119875b

Total 5 1681 249 (101ndash617) 0000 271 (102ndash715) 0000 231 (110ndash485) 0000 164 (095ndash281) 0024Ethnicity

Asian 2 1127 275 (015ndash5189) 0001 305 (017ndash5374) 0001 291 (016ndash5275) 0000 114 (089ndash146) 0329Turkish 3 554 269 (126ndash575) 0052 288 (114ndash730) 0070 250 (172ndash363) 0669 208 (076ndash567) 0030

GenotypingPCR-RFLP 3 1359 207 (056ndash767) 0000 128 (064ndash254) 0108 176 (068ndash457) 0001 111 (088ndash142) 0549PCR-SSCP 2 322 397 (047ndash3324) 0014 766 (328ndash1789) 0384 458 (070ndash3018) 0024 286 (112ndash733) 0134aNumber of studiesb119875 value of119876 test for heterogeneity

Note weights are from random effects analysis

Study ID

271 (102 715)

144 (067 310)

306 (086 1084)

080 (047 134)

OR (95 CI)

616 (231 1641)

1467 (271 7950)

10000

2243

1808

2427

Weight ()

2062

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

Study ID

231 (110 485)

266 (124 573)

294 (163 532)

074 (045 123)

OR (95 CI)

1386 (287 6704)

201 (108 372)

10000

2037

2235

2327

Weight ()

1194

2206

00149 1 67

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(b)

Figure 2 Forest plots of urolithiasis associated with distribution of genotypic frequencies of rs1126616 (a) Homozygote model (b) dominantmodel

BioMed Research International 5

Table 4 Summary of SMD and 95 CI for associations between OPN level and urolithiasis risk

Polymorphism Subgroup 119873a Sample size SMD (95 CI) 119875 value 119875 heterogeneity

UrineAll 7 1754 minus055 (minus130ndash020) 0151 lt00001

Large sample size 2 1522 minus078 (minus089 to minus067) lt00001 0749Asian populations 5 1671 minus065 (minus161ndash031) 0182 lt00001

Serum All 3 1270 minus147 (minus189 to minus104) lt00001 001aThe number of studies

Note weights are from random effects analysis

Study ID

2

1

271 (102 715)

144 (067 310)

306 (086 1084)

616 (231 1641)

080 (047 134)

288 (114 730)

OR (95 CI)

305 (017 5374)

1467 (271 7950)

10000

2243

1808

2062

2427

6114

Weight ()

3886

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 906 P = 0001)

Subtotal (I2 = 624 P = 0070)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

2

Study ID

1

271 (102 715)

766 (328 1789)

128 (064 254)

080 (047 134)

616 (231 1641)

1467 (271 7950)

144 (067 310)

306 (086 1084)

OR (95 CI)

10000

3521

6479

2427

2062

1459

2243

1808

Weight ()

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 551 P = 0108)

Subtotal (I2 = 00 P = 0384)

Yamate et al 2000

oG 2010gebakan et al

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

(b)

Figure 3 Forest plots of subgroup analysis of urolithiasis associated with the distribution of genotypic frequencies of rs1126616 in thehomozygote model (a) stratified by ethnicity (b) stratified by genotyping method

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 3: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

BioMed Research International 3

Table 2 Characteristics of individual studies included in the meta-analysis of OPN level and urolithiasis

OPN level in urineYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 0028 0021 684 0048 00272012 Salama et al [24] Asian Saudi Arabia 25 15 2167 37 10 5888 172012 Kolbach et al [23] Caucasian USA 26 13 25 15 13 40 22010 Liu et al [16] Asian China 496 249 0029 0024 247 0050 00312003 Huang et al [20] Asian China 64 32 1018 131 32 559 1081999 Yasui et al [21] Asian Japan 60 47 3577 2792 13 8879 35281996 Bautista et al [22] Caucasian England 57 34 076 071 23 079 076

OPN level in serumYear Author Ethnicity Country Sample size Case Mean SD Control Mean SD2013 Safarinejad et al [26] Asian Iran 1026 342 42 16 684 64 162013 Tugcu et al [25] Caucasian Turkey 219 127 45 28 92 83 372012 Salama et al [24] Asian Saudi Arabia 25 15 1120 230 10 2025 380

Articles searched by

For urolithiasis OPN level

(n = 28)

(n = 10)(n = 5)

(n = 4)

(n = 8)

(n = 5)

(n = 7)

For

Citations identified and screened

Not case-control study(n = 8)Not related to Rs1126616

Review

Eligible articles

hand

Figure 1 Flow diagram of literature search and selection process

(RFLP) and PCR-single-strand conformation polymorphism(SSCP) Urolithiasis was confirmed by ultrasonography orradiography in all studies

32 Meta-Analysis Results The main results of the meta-analysis of the association between OPN gene polymorphismrs1126616 and urolithiasis are listed in Table 3 Overall thepooled OR was 249 (95 CI 101ndash617) for heterozygotemodel 271 (95 CI 102ndash715) for homozygote model 231(95 CI 110ndash485) for dominant model and 164 (95 CI095ndash281) for recessive model (Figure 2) When the studieswere stratified by ethnicity the results were positive only inTurkish populations (heterozygote model pooled OR = 26995 CI 126ndash575 homozygote model pooled OR = 28895 CI 114ndash730 dominant model pooled OR = 250 95CI 172ndash363 Figure 3(a)) Moreover when the studies werestratified by genotyping method the result was significantonly in the PCR-SSCPmethod with a pooledORof 766 (95CI 328ndash1789) for the homozygote model and 286 (95 CI112ndash733) for the recessive model (Figure 3(b))

For the association of OPN level the detailed results areshown inTable 4Thepooled SMDwasminus055 (95CIminus130ndash020) for the association between OPN levels in urine and

urolithiasis risk (Figure 4(a))When the studies onOPN levelin urine were stratified by ethnicity the results were negativein both the Asian and Turkish subgroups with a pooled SMDof minus149 (95 CI minus379ndash081) and minus055 (95 CI minus130ndash020) However the results were positive when the studieswere stratified by sample size and a lowOPN level was foundin urine of urolithiasis patients in large sample size subgroupFurthermore our results indicated that reduced OPN levelwas evident in the serum of urolithiasis patients comparedwith normal controls (SMD = minus147 95 CI minus189 to minus104Figure 4(b))

33 Test of Heterogeneity For OPN gene polymorphismrs1126616 association a significant heterogeneity wasobserved in all the genetic models However heterogeneitydecreased when subgroup analyses were conducted by eth-nicity or by using genotyping methods For the OPN levelsassociation in urine or serum heterogeneity between studieswas also observed in overall comparisons as well as in sub-group analyses However heterogeneity was also reduced bysubgroup analyses We failed to confirm the source of theheterogeneity because of overmuch confounding factors

4 BioMed Research International

Table 3 Meta-analysis results of the association between OPN C6982T polymorphism and urolithiasis risk

119873a Sample size CT versus CC 119875b TT versus CC 119875b CTTT versus CC 119875b TT versus CTCC 119875b

Total 5 1681 249 (101ndash617) 0000 271 (102ndash715) 0000 231 (110ndash485) 0000 164 (095ndash281) 0024Ethnicity

Asian 2 1127 275 (015ndash5189) 0001 305 (017ndash5374) 0001 291 (016ndash5275) 0000 114 (089ndash146) 0329Turkish 3 554 269 (126ndash575) 0052 288 (114ndash730) 0070 250 (172ndash363) 0669 208 (076ndash567) 0030

GenotypingPCR-RFLP 3 1359 207 (056ndash767) 0000 128 (064ndash254) 0108 176 (068ndash457) 0001 111 (088ndash142) 0549PCR-SSCP 2 322 397 (047ndash3324) 0014 766 (328ndash1789) 0384 458 (070ndash3018) 0024 286 (112ndash733) 0134aNumber of studiesb119875 value of119876 test for heterogeneity

Note weights are from random effects analysis

Study ID

271 (102 715)

144 (067 310)

306 (086 1084)

080 (047 134)

OR (95 CI)

616 (231 1641)

1467 (271 7950)

10000

2243

1808

2427

Weight ()

2062

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

Study ID

231 (110 485)

266 (124 573)

294 (163 532)

074 (045 123)

OR (95 CI)

1386 (287 6704)

201 (108 372)

10000

2037

2235

2327

Weight ()

1194

2206

00149 1 67

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(b)

Figure 2 Forest plots of urolithiasis associated with distribution of genotypic frequencies of rs1126616 (a) Homozygote model (b) dominantmodel

BioMed Research International 5

Table 4 Summary of SMD and 95 CI for associations between OPN level and urolithiasis risk

Polymorphism Subgroup 119873a Sample size SMD (95 CI) 119875 value 119875 heterogeneity

UrineAll 7 1754 minus055 (minus130ndash020) 0151 lt00001

Large sample size 2 1522 minus078 (minus089 to minus067) lt00001 0749Asian populations 5 1671 minus065 (minus161ndash031) 0182 lt00001

Serum All 3 1270 minus147 (minus189 to minus104) lt00001 001aThe number of studies

Note weights are from random effects analysis

Study ID

2

1

271 (102 715)

144 (067 310)

306 (086 1084)

616 (231 1641)

080 (047 134)

288 (114 730)

OR (95 CI)

305 (017 5374)

1467 (271 7950)

10000

2243

1808

2062

2427

6114

Weight ()

3886

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 906 P = 0001)

Subtotal (I2 = 624 P = 0070)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

2

Study ID

1

271 (102 715)

766 (328 1789)

128 (064 254)

080 (047 134)

616 (231 1641)

1467 (271 7950)

144 (067 310)

306 (086 1084)

OR (95 CI)

10000

3521

6479

2427

2062

1459

2243

1808

Weight ()

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 551 P = 0108)

Subtotal (I2 = 00 P = 0384)

Yamate et al 2000

oG 2010gebakan et al

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

(b)

Figure 3 Forest plots of subgroup analysis of urolithiasis associated with the distribution of genotypic frequencies of rs1126616 in thehomozygote model (a) stratified by ethnicity (b) stratified by genotyping method

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 4: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

4 BioMed Research International

Table 3 Meta-analysis results of the association between OPN C6982T polymorphism and urolithiasis risk

119873a Sample size CT versus CC 119875b TT versus CC 119875b CTTT versus CC 119875b TT versus CTCC 119875b

Total 5 1681 249 (101ndash617) 0000 271 (102ndash715) 0000 231 (110ndash485) 0000 164 (095ndash281) 0024Ethnicity

Asian 2 1127 275 (015ndash5189) 0001 305 (017ndash5374) 0001 291 (016ndash5275) 0000 114 (089ndash146) 0329Turkish 3 554 269 (126ndash575) 0052 288 (114ndash730) 0070 250 (172ndash363) 0669 208 (076ndash567) 0030

GenotypingPCR-RFLP 3 1359 207 (056ndash767) 0000 128 (064ndash254) 0108 176 (068ndash457) 0001 111 (088ndash142) 0549PCR-SSCP 2 322 397 (047ndash3324) 0014 766 (328ndash1789) 0384 458 (070ndash3018) 0024 286 (112ndash733) 0134aNumber of studiesb119875 value of119876 test for heterogeneity

Note weights are from random effects analysis

Study ID

271 (102 715)

144 (067 310)

306 (086 1084)

080 (047 134)

OR (95 CI)

616 (231 1641)

1467 (271 7950)

10000

2243

1808

2427

Weight ()

2062

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

Study ID

231 (110 485)

266 (124 573)

294 (163 532)

074 (045 123)

OR (95 CI)

1386 (287 6704)

201 (108 372)

10000

2037

2235

2327

Weight ()

1194

2206

00149 1 67

Overall (I2 = 818 P = 0000)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(b)

Figure 2 Forest plots of urolithiasis associated with distribution of genotypic frequencies of rs1126616 (a) Homozygote model (b) dominantmodel

BioMed Research International 5

Table 4 Summary of SMD and 95 CI for associations between OPN level and urolithiasis risk

Polymorphism Subgroup 119873a Sample size SMD (95 CI) 119875 value 119875 heterogeneity

UrineAll 7 1754 minus055 (minus130ndash020) 0151 lt00001

Large sample size 2 1522 minus078 (minus089 to minus067) lt00001 0749Asian populations 5 1671 minus065 (minus161ndash031) 0182 lt00001

Serum All 3 1270 minus147 (minus189 to minus104) lt00001 001aThe number of studies

Note weights are from random effects analysis

Study ID

2

1

271 (102 715)

144 (067 310)

306 (086 1084)

616 (231 1641)

080 (047 134)

288 (114 730)

OR (95 CI)

305 (017 5374)

1467 (271 7950)

10000

2243

1808

2062

2427

6114

Weight ()

3886

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 906 P = 0001)

Subtotal (I2 = 624 P = 0070)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

2

Study ID

1

271 (102 715)

766 (328 1789)

128 (064 254)

080 (047 134)

616 (231 1641)

1467 (271 7950)

144 (067 310)

306 (086 1084)

OR (95 CI)

10000

3521

6479

2427

2062

1459

2243

1808

Weight ()

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 551 P = 0108)

Subtotal (I2 = 00 P = 0384)

Yamate et al 2000

oG 2010gebakan et al

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

(b)

Figure 3 Forest plots of subgroup analysis of urolithiasis associated with the distribution of genotypic frequencies of rs1126616 in thehomozygote model (a) stratified by ethnicity (b) stratified by genotyping method

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 5: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

BioMed Research International 5

Table 4 Summary of SMD and 95 CI for associations between OPN level and urolithiasis risk

Polymorphism Subgroup 119873a Sample size SMD (95 CI) 119875 value 119875 heterogeneity

UrineAll 7 1754 minus055 (minus130ndash020) 0151 lt00001

Large sample size 2 1522 minus078 (minus089 to minus067) lt00001 0749Asian populations 5 1671 minus065 (minus161ndash031) 0182 lt00001

Serum All 3 1270 minus147 (minus189 to minus104) lt00001 001aThe number of studies

Note weights are from random effects analysis

Study ID

2

1

271 (102 715)

144 (067 310)

306 (086 1084)

616 (231 1641)

080 (047 134)

288 (114 730)

OR (95 CI)

305 (017 5374)

1467 (271 7950)

10000

2243

1808

2062

2427

6114

Weight ()

3886

1459

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 906 P = 0001)

Subtotal (I2 = 624 P = 0070)

Yamate et al 2000

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

oG 2010gebakan et al

(a)

Note weights are from random effects analysis

2

Study ID

1

271 (102 715)

766 (328 1789)

128 (064 254)

080 (047 134)

616 (231 1641)

1467 (271 7950)

144 (067 310)

306 (086 1084)

OR (95 CI)

10000

3521

6479

2427

2062

1459

2243

1808

Weight ()

00126 1 795

Overall (I2 = 818 P = 0000)

Subtotal (I2 = 551 P = 0108)

Subtotal (I2 = 00 P = 0384)

Yamate et al 2000

oG 2010gebakan et al

Tekin et al 2012

Tugcu et al 2013

Safarinejad et al 2013

(b)

Figure 3 Forest plots of subgroup analysis of urolithiasis associated with the distribution of genotypic frequencies of rs1126616 in thehomozygote model (a) stratified by ethnicity (b) stratified by genotyping method

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 6: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

6 BioMed Research International

Note weights are from random effects analysis

Study ID

minus055 (minus130 020)

minus004 (minus057 049)

minus179 (minus249 minus110)

minus079 (minus093 minus066)

minus1210 (minus1568 minus851)

SMD (95 CI)

minus076 (minus094 minus058)

382 (299 466)

minus085 (minus165 minus004)

10000

1635

1544

1770

352

Weight ()

1761

1460

1477

0minus157 157

Overall (I2 = 965 P = 0000)

Safarinejad et al 2013

Bautista et al 1996

Yasui et al 1999

Huang et al 2003

Liu et al 2010

Salama et al 2012

Kolbach et al 2012

(a)

Note weights are from random effects analysis

Study ID

minus147 (minus189 minus104)

minus118 (minus147 minus089)

SMD (95 CI)

minus304 (minus423 minus185)

minus138 (minus152 minus123)

10000

4133

Weight ()

1021

4846

minus423 0 423

Overall (I2 = 781 P = 0010)

Safarinejad et al 2013

Tugcu et al 2013

Salama et al 2012

(b)

Figure 4 Forest plots of urolithiasis associated with OPN levels (a) OPN levels in urine (b) OPN levels in serum

34 SensitivityAnalysis Sensitivity analysiswas used to detectthe influence of each study on the pooled OR by repeatingthe meta-analysis while omitting a single study each time[29] Figure 5 shows the sensitivity analyses for OPN genepolymorphism association for the homozygote model in theoverall population thereby demonstrating that no individualstudy significantly affected the pooled OR The sensitivityanalysis indicated that our results were reliable

35 Publication Bias Beggrsquos funnel plot was utilised to assessthe publication bias of the literature Figure 6 displays afunnel plot for the urineOPN levels association thereby indi-cating the absence of significant publication bias which wasconfirmed by Eggerrsquos test (119875 = 0854) Moreover no

significant publication bias was detected for serum OPNlevels by Eggerrsquos test (119875 = 0563) For the OPN genepolymorphism association no significant publication biaswas detected as well (dominant model Beggrsquos test 119875 = 0221Eggerrsquos test 119875 = 0052)

4 Discussion

Urolithiasis as a complex and multifactorial disease is oneof the most prevalent disorders in the urological system withincreasing incidence Approximately 5 of females and 12ofmales are likely to develop urolithiasis during their lifetime[30] A growing body of evidence shows that organic sub-stances in addition to inorganic substancesmay significantly

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 7: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

BioMed Research International 7

minus024 099002 196 260

1

2

3

4

5

Study omittedMeta-analysis random effects estimates (linear form)

Figure 5 Sensitivity analysis of urolithiasis risk associated with theOPN polymorphism under the homozygote model

influence the development of urolithiasis Osteopontin acomponent of the urinary stone matrix is recognised as apotential protectant against urolithiasis [31] Thus mutationsin the gene that directs the synthesis ofOPNmight contributeto urolithiasis formation as a genetic factor Single nucleotidepolymorphisms have been identified as a powerful tool forpredicting complex diseases in recent years [32] Howeverprevious genetic epidemiological studies about the associ-ation between OPN gene polymorphism rs1126616 and therisk of calcium urolithiasis are limited and the results ofthese studies were inconclusive For instance Tugcu et aladvocated that the T allele of OPN gene polymorphismrs1126616 was a risk factor for urolithiasis [25] InterestinglySafarinejad and his colleagues held an opposite opinion [26]

Meta-analysis is a powerful tool that can provide morereliable results than a single study and explain controversialconclusions [33] Thus we used a meta-analysis to clarifythe possible association between the OPN gene polymor-phism rs1126616 and the risk of urolithiasis Moreover theassociation between OPN levels and urolithiasis was alsoevaluated To the best of our knowledge no meta-analysiswas conducted on this subject before Finally for the OPNC6982T polymorphism association our results indicated thatthe T allele of C6982T polymorphism might be a risk factorfor urolithiasis When stratified by ethnicity the results werepositive only in Turkish Moreover the results were signifi-cant only in PCR-SSCP subgroup when stratified by genotyp-ing method For the OPN level association a low OPN levelwas found in the urine of urolithiasis patients in large samplesize when stratification was performed according to samplesizeMoreover studies confirmed thatOPN level in the serumof urolithiasis patients was lower than normal controls

Previous studies showed that the occurrence of urolithia-sis in particular geographical areas is statistically higher thanelsewhere in particular countries [34 35] suggesting that theincidence of gene polymorphisms can notably vary amongdifferent racial populations because of ethnic differences Asa result stratified analysis was performed by ethnicity inthis meta-analysis Although the exact mechanism was notwell known the results above may be partially explained

Beggrsquos funnel plot with pseudo 95 confidence limits

SMD

se of SMD0 05 1 15 2

minus15

minus10

minus5

0

5

Figure 6 Beggrsquos funnel plot for publication bias test of urolithiasisrisk associated with the urine OPN levels

First the sample size was relatively small which may notreveal the real association because of limited statistical powerParticularly the research on theTurkish population cannot begeneralised to theCaucasian populationsMoreover differentgenetic backgrounds and environmental contexts might notbe totally reflected by the differences among ethnic groups asshown by the identical results obtained in Asian and Turkishsubgroups Furthermore the diversity of variable factorssuch as different matching criteria and selection bias shouldbe taken into consideration

In recent years various molecular techniques have beenused as tools in genotyping However different researchmethods may affect the conclusions Therefore we also con-ducted a subgroup analysis by using genotyping methods Inthis meta-analysis both PCR-RFLP and PCR-SSCP wereapplied to analyse the association between OPN gene poly-morphism rs1126616 and urolithiasis However the subgroupanalysis was significant only in PCR-SSCP As a highly sensi-tive technique PCR-SSCP is widely applied in the detectionof small sequence changes and point mutations [36] Never-theless diverse methods have advantages in different aspectswhich might constitute a source of bias As a result the meta-analysis results would be more accurate if the genotypingmethods were unified

Osteopontin is a multifunctional protein expressed ina variety of different cell types in the human body and issynthesised by the kidney and secreted into urine by epithelialcells including those in loops of Henle distal convolutedtubules and papillary epithelia [12 37] Notably OPN levelsare vital in the mechanism of urolithiasis therefore we alsoevaluated the relationships between OPN levels in urine orserum and urolithiasis Previous studies suggested that highurinary excretion of osteopontin may play an importantprotective role in preventing calcium urolithiasis formationwhich was further confirmed in our meta-analysis by thelower levels of OPN in both urine (stratified by sample size)and serum of urolithiasis patients than those of normal con-trols Possibly the incorporation of OPN into growing stonesmight lead to lessOPN in patients [38] However the accuratemechanism requires further exploration

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 8: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

8 BioMed Research International

Despite the overall robust statistical evidence generatedthrough this analysis a number of limitations were identifiedFirst some articles involved in the OPN gene polymorphismassociation are not in accord with the HWE which may beattributed to the limited sample size and difference in eth-nicity Meanwhile significant heterogeneity between studieswas observed and such heterogeneity could be reduced bysubgroup analysis However as the firstmeta-analysis regard-ing the comprehensive assessment of the association thenumber of published studies was limited and sample size wasrelatively small As a result theHWEviolation and significantheterogeneity were inevitable to some degree Moreover ourresults were based on unadjusted estimates Consequentlya more precise analysis could be performed in the pres-ence of all individual raw data which could allow for theadjustment of other covariates including age sex drinkingstatus and cigarette consumption Third urolithiasis resultsfrom complex interactions between a variety of genetic andenvironmental factors thereby suggesting that urolithiasissusceptibility would not be influenced by any single geneWe cannot exclude the fact that other genetic polymorphismsare linked with rs1126616 or even directly contribute tourolithiasis Thus further research with combined effectsanalysis is required Last but not least because of the limitedstudies involved the significant difference of results should beinterpreted cautiously Accordingly more studies should beconducted to provide a more definitive conclusion To illus-trate the populations in this study only included Asians andTurkish population Thus populations of other ethnicitiesshould be involved in future studies

5 Conclusion and Recommendation

Despite these limitations the results of the present meta-analysis suggest that the carriers of the T allele had higherurolithiasis risk than the noncarriers especially in individualsof Turkish ethnicity In addition lower OPN levels weredetected in urine and serum of urolithiasis patients than nor-mal controls which proved the important role of OPN in thedevelopment of urolithiasis Our research might provide newinsight into the aetiology of urolithiasis The OPN gene poly-morphism andOPN level might be an index for detecting therisk of urolithiasis which could be applied in early screeningand prediction of urolithiasis Nevertheless several problemsrequire solutions though we believe that the important rolesof OPN gene polymorphism rs1126616 and OPN level arepromising To develop a more comprehensive understand-ing of the relationship between OPN gene polymorphismand urolithiasis sensibility the following recommendationsshould be considered (1) High-quality studies by standard-ised unbiasedmethods are needed and these studies can offermore detailed individual data (2) A more comprehensiveand generalizable conclusion can be achieved in studiesthat involve various ethnic groups (3) Combined effects ofdifferent gene polymorphisms need to be analysed Becausethe genetic background of stone formation is a complicatedissue and includes single-candidate genes and the epigeneticprocess a single gene is difficult to be identified as responsiblefor urolithiasis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xiao Li Kang Liu and Yongsheng Pan contributed equally tothis work Jie Li and Changjun Yin equally contributed to thiswork

Acknowledgments

Thisworkwas supported by the project funded by the PriorityAcademic Program Development (PAPD) of Jiangsu HigherEducation Institutions by the Jiangsu Provincial SpecialProgram of Medical Science (BL2012027) by the Programfor Development of Innovative Research Team in the FirstAffiliated Hospital of Nanjing Medical University and by theNational Natural Science Foundation of China (Grant nos81171963 81201998 and 81201571)

References

[1] S Lewandowski and A L Rodgers ldquoIdiopathic calcium oxalateurolithiasis risk factors and conservative treatmentrdquo ClinicaChimica Acta vol 345 no 1-2 pp 17ndash34 2004

[2] D R Basavaraj C S Biyani A J Browning and J J CartledgeldquoThe role of urinary kidney stone inhibitors and promotors inthe pathogenesis of calcium containing renal stonesrdquo EAU-EBUUpdate Series vol 5 no 3 pp 126ndash136 2007

[3] R Pramanik J R Asplin M E Jackson and J C Williams JrldquoProtein content of human apatite and brushite kidney stonessignificant correlation with morphologic measuresrdquo UrologicalResearch vol 36 no 5 pp 251ndash258 2008

[4] L Addadi S Weiner and M Geva ldquoOn how proteins interactwith crystals and their effect on crystal formationrdquo Zeitschriftfur Kardiologie vol 90 no 3 pp 92ndash98 2001

[5] S Weiner and L Addadi ldquoAcidic macromolecules of miner-alized tissues the controllers of crystal formationrdquo Trends inBiochemical Sciences vol 16 no 7 pp 252ndash256 1991

[6] J A Wesson R J Johnson M Mazzali et al ldquoOsteopontinis a critical inhibitor of calcium oxalate crystal formation andretention in renal tubulesrdquo Journal of the American Society ofNephrology vol 14 no 1 pp 139ndash147 2003

[7] B Gao T Yasui Y Itoh et al ldquoAssociation of osteopontin genehaplotypes with nephrolithiasisrdquo Kidney International vol 72no 5 pp 592ndash598 2007

[8] C J Danpure ldquoGenetic disorders and urolithiasisrdquoTheUrologicClinics of North America vol 27 no 2 pp 287ndash299 2000

[9] M Mazzali T Kipari V Ophascharoensuk J A Wesson RJohnson and J Hughes ldquoOsteopontinmdasha molecule for allseasonsrdquo Quarterly Journal of Medicine vol 95 no 1 pp 3ndash132002

[10] G La Torre S Boccia and G Ricciardi ldquoGlutathione 119878-trans-feraseM1 status and gastric cancer risk ameta-analysisrdquoCancerLetters vol 217 no 1 pp 53ndash60 2005

[11] L W Fisher D A Torchia B Fohr M F Young and N SFedarko ldquoFlexible structures of SIBLING proteins bone sialo-protein and osteopontinrdquo Biochemical and Biophysical ResearchCommunications vol 280 no 2 pp 460ndash465 2001

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 9: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

BioMed Research International 9

[12] T Yasui K Fujita S Sasaki et al ldquoExpression of bone matrixproteins in urolithiasis model ratsrdquo Urological Research vol 27no 4 pp 255ndash261 1999

[13] A C Forton M A Petri D Goldman and K E Sullivan ldquoAnosteopontin (SPP1) polymorphism is associated with systemiclupus erythematosusrdquo Human mutation vol 19 no 4 p 4592002

[14] T Yamate H Tsuji N Amasaki M Iguchi T Kurita and KKohri ldquoAnalysis of osteopontin DNA in patients with urolithi-asisrdquo Urological Research vol 28 no 3 pp 159ndash166 2000

[15] B Gao T Yasui A Okada K Tozawa Y Hayashi and K KohrildquoA polymorphism of the osteopontin gene is related to urinarycalcium stonesrdquoThe Journal of Urology vol 174 no 4 part 1 pp1472ndash1476 2005

[16] C-C Liu S-PHuang L-Y Tsai et al ldquoThe impact of osteopon-tin promoter polymorphisms on the risk of calcium urolithia-sisrdquo Clinica Chimica Acta vol 411 no 9-10 pp 739ndash743 2010

[17] R DerSimonian and R Kacker ldquoRandom-effects model formeta-analysis of clinical trials an updaterdquo Contemporary Clini-cal Trials vol 28 no 2 pp 105ndash114 2007

[18] M Egger G D Smith M Schneider and C Minder ldquoBiasin meta-analysis detected by a simple graphical testrdquo BritishMedical Journal vol 315 no 7109 pp 629ndash634 1997

[19] S W Guo and E A Thompson ldquoPerforming the exact test ofHardy-Weinberg proportion for multiple allelesrdquo Biometricsvol 48 no 2 pp 361ndash372 1992

[20] H-S Huang M-C Ma C-F Chen and J Chen ldquoLipid perox-idation and its correlations with urinary levels of oxalate citricacid and osteopontin in patients with renal calcium oxalatestonesrdquo Urology vol 62 no 6 pp 1123ndash1128 2003

[21] T Yasui K Fujita YHayashi et al ldquoQuantification of osteopon-tin in the urine of healthy and stone-forming menrdquo UrologicalResearch vol 27 no 4 pp 225ndash230 1999

[22] D S Bautista J Denstedt A F Chambers and J F HarrisldquoLow-molecular-weight variants of osteopontin generated byserine proteinases in urine of patients with kidney stonesrdquoJournal of Cellular Biochemistry vol 61 no 3 pp 402ndash409 1996

[23] A M Kolbach O Afzal B Halligan E Sorokina J GKleinman and J A Wesson ldquoRelative deficiency of acidicisoforms of osteopontin from stone former urinerdquo UrologicalResearch vol 40 no 5 pp 447ndash454 2012

[24] R H M Salama A Alghasham M S Mostafa and A E AEl-Moniem ldquoBone morphogenetic protein-2 will be a novelbiochemical marker in urinary tract infections and stoneformationrdquoClinical Biochemistry vol 45 no 10-11 pp 766ndash7692012

[25] V Tugcu A Simsek T Tarhan et al ldquoOPN gene polymorphism(Ala250) and lower serum OPN levels are associated withurolithiasisrdquo Renal Failure vol 35 no 6 pp 825ndash829 2013

[26] M R Safarinejad N Shafiei and S Safarinejad ldquoAssociationbetween polymorphisms in osteopontin gene (SPP1) and firstepisode calcium oxalate urolithiasisrdquo Urolithiasis vol 41 no 4pp 303ndash313 2013

[27] G Tekin P Ertan G Horasan and A Berdeli ldquoSPP1 gene poly-morphisms associated with nephrolithiasis in Turkish pediatricpatientsrdquo Urology Journal vol 9 no 4 pp 640ndash647 2012

[28] B Gogebakan Y Z Igci A Arslan et al ldquoAssociation betweenthe T-593A and C6982T polymorphisms of the osteopontingene and risk of developing nephrolithiasisrdquoArchives ofMedicalResearch vol 41 no 6 pp 442ndash448 2010

[29] F Liu L Liu B Li et al ldquop73 G4C14-A4T14 polymorphism andcancer risk a meta-analysis based on 27 case-control studiesrdquoMutagenesis vol 26 no 4 pp 573ndash581 2011

[30] D Li J Liu J Ren L Yan H Liu and Z Xu ldquoMeta-analysisof the urokinase gene 31015840-UTR TC polymorphism and sus-ceptibility to urolithiasisrdquo Biomedical Reports vol 1 no 3 pp369ndash374 2013

[31] J G Kleinman J A Wesson and J Hughes ldquoOsteopontin andcalcium stone formationrdquoNephron Physiology vol 98 no 2 ppp43ndashp47 2004

[32] T Arcidiacono A Terranegra R Biasion L Soldati and GVezzoli ldquoCalcium kidney stones Diagnostic and preventiveprospectsrdquo Giornale Italiano di Nefrologia vol 24 no 6 pp535ndash546 2007

[33] M R Munafo and J Flint ldquoMeta-analysis of genetic associationstudiesrdquo Trends in Genetics vol 20 no 9 pp 439ndash444 2004

[34] JM Soucie R J CoatesWMcClellanHAustin andMThunldquoRelation between geographic variability in kidney stonesprevalence and risk factors for stonesrdquo American Journal ofEpidemiology vol 143 no 5 pp 487ndash495 1996

[35] K K Stamatelou M E Francis C A Jones L M Nyberg Jrand G C Curhan ldquoTime trends in reported prevalence ofkidney stones in the United States 1976ndash1994rdquo Kidney Interna-tional vol 63 no 5 pp 1817ndash1823 2003

[36] M Orita H Iwahana H Kanazawa K Hayashi and TSekiya ldquoDetection of polymorphisms of human DNA by gelelectrophoresis as single-strand conformation polymorphismsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 86 no 8 pp 2766ndash2770 1989

[37] RW EWatts ldquoIdiopathic urinary stone disease possible poly-genic aetiological factorsrdquo Quarterly Journal of Medicine vol98 no 4 pp 241ndash246 2005

[38] S R Khan J M Johnson A B Peck J G Cornelius and P AGlenton ldquoExpression of osteopontin in rat kidneys inductionduring ethylene glycol induced calciumoxalate nephrolithiasisrdquoThe Journal of Urology vol 168 no 3 pp 1173ndash1181 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 10: Review Article Roles of Osteopontin Gene Polymorphism ...downloads.hindawi.com/journals/bmri/2015/315043.pdf · Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom