RESEARCH ARTICLE

Myeloperoxidase G463A polymorphism and riskof lung cancer

Junrui Li & Yingju Fu & Baochun Zhao & Ying Xiao &

Ruiying Chen

Received: 12 July 2013 /Accepted: 13 August 2013 /Published online: 25 August 2013# International Society of Oncology and BioMarkers (ISOBM) 2013

Abstract Myeloperoxidase (MPO) is a phase I enzymeplaying a crucial role in metabolically activating a wide rangeof procarcinogens, such as polycyclic aromatic hydrocarbonsand aromatic amines. The G463A polymorphism in the pro-moter region of the MPO gene has been indicated in lungcancer risk. To investigate the precise association of MPOG463A polymorphism with the lung cancer risk, weperformed this comprehensive meta-analysis with large avail-able data published to date. The included 24 individual studiesinvolving a total of 8,313 cases and 8,728 controls wereidentified by searching the PubMed, Embase, and Wanfangdatabases. The crude odds ratios (ORs) and the corresponding95 % confidence intervals (CIs) were calculated to estimatethe association. Stratified analyses by ethnicity, source ofcontrols, smoking status, and histological types were alsoconducted. Overall, the MPO G463A polymorphism wasnegatively related to the development of lung cancer in thefollowing genetic models (Avs. G, OR=0.90, 95%CI=0.82–0.99, POR=0.029; GA vs. GG, OR=0.89, 95 % CI=0.80–0.98, POR=0.022; AA+GA vs. GG, OR=0.89, 95 % CI=0.81–0.98, POR=0.023). Stratified analyses by ethnicity indi-cated that the variant genotype ofMPOG463Awas associated

with a decreased risk of lung cancer in Asians and Caucasians.Similar findings were observed among the smokers andpopulation-based case–control studies. The MPO G463Apolymorphism seemed to exert no effect on lung adenocarci-noma and squamous cell carcinoma. The comprehensivemeta-analysis shows that the polymorphism of MPO G463Ais a protective factor for lung cancer, particularly among thepopulations of Asians, Caucasians, and smokers.

Keywords Myeloperoxidase . Lung cancer .

Single-nucleotide polymorphism .Meta-analysis

Introduction

Lung cancer is one of the most common cancers and theleading cause of cancer-related death worldwide [1]. Tobaccosmoking, alcohol consumption, radon radiation, and chronicairway inflammation are well-established risk factors for lungcancer [2, 3]. However, not all individuals exposed to theknown risk factors develop lung cancer, which suggests thatthere are many other factors including genetic predispositionresponsible for the lung carcinogenesis. The single-nucleotidepolymorphisms of phospholipase D1, Rad18, interleukin-23receptor, and so on are related to the lung cancer risk [4–6].

Myeloperoxidase (MPO) is an oxidative lysosomal en-zyme, which is critical in bioactivating a wide range of spe-cific procarcinogens, such as polycyclic aromatic hydrocar-bons and aromatic amines [7, 8]. It is released from cytoplas-mic granules of neutrophils and monocytes by a degranulationprocess and reacts with the H2O2 [7]. The MPO gene islocated on chromosome 17q23.1 with a total of 11 intronsand 12 exons [8, 9]. The polymorphism of MPO G463A(rs2333227) within the MPO −463 gene promoter is one ofthe most extensively studied single-nucleotide polymor-phisms. It has been shown to be involved in the development

J. Li (*) : B. ZhaoDepartment of Infectious Disease, Tangshan Worker’s Hospital, No.27 Wenhua Road, Tangshan, Hebei 063000, Chinae-mail: junruili@aliyun.com

Y. FuDepartment of Emergency Internal Medicine, Tangshan Worker’sHospital, Tangshan, Hebei 063000, China

Y. XiaoDepartment of Oncology, Tangshan Worker’s Hospital, Tangshan,Hebei 063000, China

R. ChenDepartment of Neurology, Affiliated Hospital of Hebei UnitedUniversity, Tangshan, Hebei 063000, China

Tumor Biol. (2014) 35:821–829DOI 10.1007/s13277-013-1113-4

of malignant tumors, such as pancreatic cancer, breast cancer,and esophageal carcinoma [10–13]. Individuals with the var-iant allele A and genotypes may be less susceptible to cancersbecause of the decreased transcriptional activity of MPO andsubsequent reduced bioactivation of procarcinogens. There-fore, we hypothesize that the MPO G463A polymorphism isnegatively associated to the risk of lung cancer. The presentmeta-analysis by pooling all currently available data wasconducted to precisely assess the role of MPO G463A muta-tion in lung carcinogenesis.

Materials and methods

Search strategy and selection criteria

We searched the PubMed, Embase, and Wanfang data-bases to identify studies on the association between theMPO G463A polymorphism and the lung cancer riskfrom the inception to July 8, 2013. The followingMedical Subject Heading terms and/or text words wereused: (“myeloperoxidase” or “MPO” or “rs2333227” or“MPO G463A”) and (“polymorphism” or “single-nucle-otide polymorphism” or “SNP” or “polymorphism, sin-gle nucleotide”) and (“lung cancer” or “lung carcino-ma”). Articles published in English or Chinese wereconsidered to be eligible for our study. Besides, publi-cations were included if they satisfied the followinginclusion criteria: (1) case–control studies, (2) paperson the relationship between the MPO G463A polymor-phism and the risk of lung cancer, and (3) sufficientinformation on the genotype frequencies of MPOG463A in cases and controls. In addition, reference ofthe original articles and reviews was also manuallysearched for other relevant studies.

Data extraction

Data were extracted from each study independently by twoauthors, and the disagreement was solved by consensus for allthe data, which were as follows: the first author's name, yearof publication, country, ethnicity, estimation of Hardy–Wein-berg equilibrium (HWE) in the control group, source of con-trols, matching criteria, genotyping methods, sample sizes ofcases and controls, histological types of lung cancer, anddistribution of genotypes in cases and controls. We contactedwith the authors of studies with inadequate information forfurther information by e-mail if possible.

Statistical analysis

The pooled odds ratios (ORs) with corresponding 95 % con-fidence intervals (CIs) were computed to assess the strength of

the association between the MPO G463A polymorphism andthe susceptibility to lung cancer. The pooled ORs were calcu-lated under the models as follows: Avs. G, AAvs. GG, GAvs.GG, AA + GAvs. GG, and AA vs. GG + GA. On account ofpossible between-study heterogeneity, both chi-square-basedQ test and I2 test were carried out [14, 15]. P >0.01 combinedwith I2<50 % suggested a lack of heterogeneity among stud-ies, and the pooled ORs were calculated by fixed effectsmodel (the Mantel–Haenszel method) [16]. The random ef-fects model (the DerSimonian and Laird method) was usedwhen the heterogeneity was significant [17]. Stratified analy-ses were also conducted according to ethnicity, source ofcontrols, smoking status, and histological types. Begg's funnelplots and Egger's linear regression test were applied to evalu-ate the potential publication bias risk among studies, and P <0.05 was considered a statistical significance [18, 19]. Allstatistical analyses were performed using the Stata 11.0 soft-ware (StataCorp LP, College Station, TX).

Results

Characteristics of eligible studies

After a comprehensive literature search of the PubMed,Embase, andWanfang databases, 24 independent studies wereidentified [20–43]. Among the 24 publications, three oneswere conducted in different populations, which were consid-ered as two individual case–control studies, respectively [20,22, 36]. As a result, there were 27 case–control studies with atotal of 8,313 cases and 8,728 controls in this meta-analysis.General characteristics of all included studies were shown inTable 1. Sixteen publications were carried out among Cauca-sians; 10, among Asians; and still 1, among Africans. Basedon the source of controls, studies on the risk of lung cancerwere mainly in hospital- and population-based case–controldesigns. Genotype frequencies among the controls in 15 of theincluded studies conformed to HWE.

Quantitative synthesis

Association between the MPO G463A polymorphismand the lung cancer risk

The pooled results were summarized in Table 2. The pooledORs implicated that the mutant allele A and genotypes of GAas well as AA + GA played protective roles in the develop-ment of lung cancer (Avs. G, OR=0.90, 95 % CI=0.82–0.99,POR=0.029; GA vs. GG, OR=0.89, 95 % CI=0.80–0.98,POR=0.022; AA + GA vs. GG, OR=0.89, 95 % CI=0.81–0.98, POR=0.023) (Table 2, Fig. 1).

822 Tumor Biol. (2014) 35:821–829

Stratified analysis by ethnicity

According to the ethnicity, we conducted stratified analysis inAsians and Caucasians, but not Africans, because of insuffi-cient available data. The variant genotype AA of MPOG463A was significantly associated with a decreased risk oflung cancer among both Asians and Caucasians (AA vs. GG,for Asians, OR=0.62, 95 % CI=0.40–0.98, POR=0.041; for

Caucasians, OR=0.96, 95 % CI=0.71–1.29, POR=0.001)(Table 2).

Stratified analysis by source of controls

The pooled ORs indicated that the MPO G463A polymor-phism exerted a protective effect on the lung carcinogenesis inpopulation-based case–control studies, but not hospital-based

Table 1 Characteristics of all studies

First author Year Ethnicity Country HWE Matching Genotypingmethods

Cases Controls Source ofcontrols

AA GA GG AA GA GG

London [20] 1997 Caucasians USA − Age, sex, ethnicity, and frequency PCR-RFLP 4 59 119 36 143 280 PCC

London [20] 1997 Africans USA − Age, sex, ethnicity, and frequency PCR-RFLP 12 74 71 23 100 121 PCC

Cascorbi[21]

2000 Caucasians Germany + Age and sex PCR-RFLP 6 49 141 6 103 161 PCC

LeMarchand[22]

2000 Caucasians USA + Age and sex PCR-RFLP 7 38 90 15 58 98 PCC

LeMarchand[22]

2000 Asians USA + Age and sex PCR-RFLP 1 23 84 7 41 115 PCC

Misra [23] 2001 Caucasians Finland + Age and frequency Probes 16 108 191 21 84 206 PCC

Lv [24] 2002 Asians China + Age, sex, and frequency PCR-SSCP 6 60 248 6 87 227 PCC

Feyler [25] 2002 Caucasians France + Age, sex, frequency, and hospital PCR-RFLP 10 42 98 13 63 96 HCC

Dally [26] 2002 Caucasians Germany + Age and sex Probes 23 173 429 17 105 218 HCC

Lu [27] 2002 Asians China + Frequency and ethnicity PCR-SSCP 6 60 248 6 87 227 PCC

Schabath[28]

2002 Caucasians USA + Age, sex, frequency, smokingstatus, and ethnicity

PCR-RFLP 14 126 235 19 157 202 PCC

Xu [29] 2002 Caucasians USA + Ethnicity PCR-RFLP 47 343 599 41 390 697 PCC

Kantarci[30]

2002 Caucasians USA + Age, sex, ethnicity, and frequency PCR-RFLP 9 106 192 15 111 181 HCC

Wu [31] 2003 Asians China ND Age and sex PCR-RFLP 3 33 62 11 48 53 PCC

Cajas-Salazar[32]

2003 Caucasians USA − Age, frequency, and sex PCR-RFLP 7 47 56 4 56 59 PCC

Chevrier[33]

2003 Caucasians France + Age, sex, hospital, and residence Probes 10 98 135 12 93 140 HCC

Liu [34] 2004 Caucasians USA ND Age and sex PCR-RFLP 44 296 490 41 386 692 PCC

Chan [35] 2005 Asians China ND Age and sex PCR-RFLP 3 28 44 2 42 118 HCC

Larsen [36] 2006 Caucasians Australia ND Age, sex, and smoke exposure PCR-RFLP 40 205 382 12 83 152 PCC

Larsen [36] 2006 Caucasians Australia ND Age, sex, and smoke exposure PCR-RFLP 40 205 382 19 127 231 HCC

Park [37] 2006 Asians Korean + Age, sex, and frequency PCR-RFLP 3 76 353 4 72 356 PCC

Zhang [38] 2007 Asians China ND Age, sex, and frequency PCR-RFLP 7 39 75 12 30 79 PCC

Yang [39] 2007 Asians Korean ND Sex and frequency PCR-RFLP 0 49 269 2 68 283 HCC

Zienolddiny[40]

2008 Caucasians Norway ND Age, sex, and smoke exposure Sequencing 34 74 150 9 109 179 PCC

Yoon [41] 2008 Asians Korean ND Age Taqman 2 31 180 3 35 175 PCC

Klinchid[42]

2009 Asians Thailand ND None PCR-RFLP 59 57 Mixed

Arslan [43] 2011 Caucasians Turkey + Ethnicity PCR-RFLP 4 35 67 21 110 136 PCC

HWE Hardy–Weinberg equilibrium,ND not determined,PCR-RFLP polymerase chain reaction–restriction fragment length polymorphism, PCR-SSCPPCR–single-strand conformation polymorphism, PCC population-based case–control study, HCC hospital-based case–control study

Tumor Biol. (2014) 35:821–829 823

Table 2 Meta-analysis results

Genetic contrast models Groups OR 95 % CI POR Heterogeneity analysis

I2 (%) P values

A vs. G Overall 0.90 0.82–0.99 0.029 60.2 <0.001

Asians 0.83 0.68–1.01 0.060 54.9 0.023

Caucasians 0.93 0.83–1.03 0.166 61.7 0.001

PCC 0.89 0.79–0.99 0.041 64.2 <0.001

HCC 0.93 0.79–1.10 0.392 51.5 0.054

Smokers 1.01 0.91–1.13 0.807 23.4 0.258

Nonsmokers 0.84 0.59–1.20 0.341 0.0 0.929

SC 0.88 0.66–1.17 0.380 72.0 0.006

AC 0.96 0.84–1.09 0.507 0.0 0.483

AA vs. GG Overall 0.89 0.69–1.14 0.362 50.3 0.002

Asians 0.62 0.40–0.98 0.041 8.0 0.369

Caucasians 0.96 0.71–1.29 0.001 60.8 0.001

PCC 0.88 0.64–1.21 0.437 57.9 0.001

HCC 0.88 0.64–1.20 0.416 12.4 0.335

Smokers 0.94 0.70–1.26 0.680 14.1 0.324

Nonsmokers 0.75 0.21–2.64 0.656 0.0 0.799

SC 1.25 0.82–1.92 0.299 0.0 0.411

AC 0.98 0.65–1.47 0.914 0.0 0.574

GA vs. GG Overall 0.89 0.80–0.98 0.022 47.4 0.004

Asians 0.85 0.68–1.07 0.171 53.2 0.029

Caucasians 0.90 0.80–1.00 0.054 43.6 0.032

PCC 0.87 0.77–0.99 0.034 53.2 0.003

HCC 0.92 0.80–1.05 0.220 34.3 0.167

Smokers 1.05 0.92–1.20 0.490 0.6 0.412

Nonsmokers 0.84 0.56–1.28 0.426 0.0 0.849

SC 0.81 0.58–1.13 0.220 71.8 0.007

AC 0.95 0.81–1.10 0.474 0.0 0.780

AA + GAvs. GG Overall 0.89 0.81–0.98 0.023 51.5 0.001

Asians 0.85 0.68–1.05 0.132 53.0 0.024

Caucasians 0.90 0.81–1.01 0.077 50.6 0.011

PCC 0.87 0.77–0.98 0.028 57.1 0.001

HCC 0.92 0.77–1.11 0.378 46.1 0.084

Smokers 0.83 0.70–0.99 0.043 54.0 0.013

Nonsmokers 0.78 0.61–1.01 0.055 0.0 0.999

SC 0.85 0.63–1.14 0.283 66.4 0.011

AC 0.93 0.81–1.08 0.357 0.0 0.667

AA vs. GG + GA Overall 0.92 0.72–1.18 0.515 48.5 0.003

Asians 0.65 0.41–1.01 0.058 0.0 0.481

Caucasians 1.00 0.75–1.34 0.997 59.9 0.001

PCC 0.92 0.67–1.25 0.582 57.3 0.001

HCC 0.91 0.67–1.23 0.535 0.0 0.445

Smokers 0.92 0.69–1.24 0.603 10.1 0.351

Nonsmokers 0.79 0.23–2.75 0.712 0.0 0.764

SC 1.28 0.84–1.96 0.244 0.0 0.547

AC 0.98 0.66–1.47 0.933 0.0 0.621

PCC population-based case–control study, HCC hospital-based case–control study, AC adenocarcinoma, SC squamous cell carcinoma,OR odds ratio,95 % CI 95 % confidence interval, POR P value for the pooled ORs

824 Tumor Biol. (2014) 35:821–829

NOTE: Weights are from random effects analysis

Overall (I-squared = 60.2%, p = 0.000)

Yang M (2007)

Liu G (2004)

Lv W (2002)

Study

Le Marchand L (2) (2000)Le Marchand L (1) (2000)

Park JH (2006)

Schabath MB (2002)

London SJ (2) (1997)

Yoon KA (2008)

Xu LL (2002)

Chevrier I (2003)

Larsen JE (1) (2006)

Kantarci OH (2002)

Chan EC (2005)

ID

Arslan S (2011)

Larsen JE (2) (2006)

Dally H (2002)

Cajas-Salazar N (2003)Wu X (2003)

Misra RR (2001)

London SJ (1) (1997)

Zhang T (2007)

Feyler A (2002)

Lu W (2002)

Cascorbi I (2000)

Zienolddiny S (2008)

0.90 (0.82, 0.99)

0.74 (0.50, 1.07)

1.14 (0.98, 1.33)

0.71 (0.51, 0.98)

0.64 (0.39, 1.07)0.69 (0.47, 1.01)

1.03 (0.74, 1.42)

0.74 (0.58, 0.95)

1.06 (0.78, 1.45)

0.84 (0.52, 1.35)

1.07 (0.93, 1.24)

1.02 (0.76, 1.37)

1.06 (0.83, 1.37)

0.85 (0.65, 1.11)

1.77 (1.08, 2.90)

OR (95% CI)

0.64 (0.44, 0.94)

1.05 (0.84, 1.30)

0.83 (0.65, 1.05)

1.04 (0.69, 1.57)0.55 (0.35, 0.86)

1.12 (0.86, 1.48)

0.74 (0.54, 1.00)

0.98 (0.64, 1.50)

0.75 (0.52, 1.08)

0.71 (0.51, 0.98)

0.68 (0.48, 0.96)

1.40 (1.06, 1.84)

100.00

3.24

5.91

3.78

%

2.273.17

3.80

4.78

3.98

2.50

5.99

4.14

4.65

4.39

2.36

Weight

3.20

5.08

4.84

2.962.66

4.41

4.00

2.82

3.34

3.78

3.61

4.35

0.90 (0.82, 0.99)

0.74 (0.50, 1.07)

1.14 (0.98, 1.33)

0.71 (0.51, 0.98)

0.64 (0.39, 1.07)0.69 (0.47, 1.01)

1.03 (0.74, 1.42)

0.74 (0.58, 0.95)

1.06 (0.78, 1.45)

0.84 (0.52, 1.35)

1.07 (0.93, 1.24)

1.02 (0.76, 1.37)

1.06 (0.83, 1.37)

0.85 (0.65, 1.11)

1.77 (1.08, 2.90)

OR (95% CI)

0.64 (0.44, 0.94)

1.05 (0.84, 1.30)

0.83 (0.65, 1.05)

1.04 (0.69, 1.57)0.55 (0.35, 0.86)

1.12 (0.86, 1.48)

0.74 (0.54, 1.00)

0.98 (0.64, 1.50)

0.75 (0.52, 1.08)

0.71 (0.51, 0.98)

0.68 (0.48, 0.96)

1.40 (1.06, 1.84)

100.00

3.24

5.91

3.78

%

2.273.17

3.80

4.78

3.98

2.50

5.99

4.14

4.65

4.39

2.36

Weight

3.20

5.08

4.84

2.962.66

4.41

4.00

2.82

3.34

3.78

3.61

4.35

1.345 1 2.9

NOTE: Weights are from random effects analysis

Overall (I-squared = 47.4%, p = 0.004)

Chevrier I (2003)

Park JH (2006)

Arslan S (2011)

Le Marchand L (2) (2000)

Feyler A (2002)Dally H (2002)

Zienolddiny S (2008)

Schabath MB (2002)

Larsen JE (1) (2006)

Study

Yang M (2007)

Lv W (2002)

Cajas-Salazar N (2003)

London SJ (1) (1997)

Cascorbi I (2000)

Yoon KA (2008)

Wu X (2003)

Chan EC (2005)

Xu LL (2002)

ID

Zhang T (2007)

Misra RR (2001)

Larsen JE (2) (2006)

Le Marchand L (1) (2000)

Lu W (2002)

Kantarci OH (2002)

London SJ (2) (1997)

Liu G (2004)

0.89 (0.81, 0.98)

1.09 (0.76, 1.58)

1.06 (0.75, 1.52)

0.65 (0.40, 1.04)

0.77 (0.43, 1.38)

0.65 (0.40, 1.06)0.84 (0.63, 1.12)

0.81 (0.56, 1.17)

0.69 (0.51, 0.93)

0.98 (0.72, 1.35)

0.76 (0.51, 1.13)

0.63 (0.43, 0.92)

0.88 (0.52, 1.51)

0.97 (0.67, 1.41)

0.54 (0.36, 0.82)

0.86 (0.51, 1.46)

0.59 (0.33, 1.04)

1.79 (0.99, 3.23)

1.02 (0.85, 1.23)

OR (95% CI)

1.37 (0.77, 2.42)

1.39 (0.98, 1.96)

0.98 (0.74, 1.29)

0.71 (0.43, 1.18)

0.63 (0.43, 0.92)

0.90 (0.64, 1.26)

1.26 (0.83, 1.92)

1.08 (0.90, 1.31)

100.00

4.03

4.21

2.92

2.21

2.915.07

4.06

4.94

4.71

%

3.64

3.96

2.53

4.00

3.59

2.57

2.26

2.17

6.90

Weight

2.28

4.31

5.33

2.77

3.96

4.46

3.47

6.74

0.89 (0.81, 0.98)

1.09 (0.76, 1.58)

1.06 (0.75, 1.52)

0.65 (0.40, 1.04)

0.77 (0.43, 1.38)

0.65 (0.40, 1.06)0.84 (0.63, 1.12)

0.81 (0.56, 1.17)

0.69 (0.51, 0.93)

0.98 (0.72, 1.35)

0.76 (0.51, 1.13)

0.63 (0.43, 0.92)

0.88 (0.52, 1.51)

0.97 (0.67, 1.41)

0.54 (0.36, 0.82)

0.86 (0.51, 1.46)

0.59 (0.33, 1.04)

1.79 (0.99, 3.23)

1.02 (0.85, 1.23)

OR (95% CI)

1.37 (0.77, 2.42)

1.39 (0.98, 1.96)

0.98 (0.74, 1.29)

0.71 (0.43, 1.18)

0.63 (0.43, 0.92)

0.90 (0.64, 1.26)

1.26 (0.83, 1.92)

1.08 (0.90, 1.31)

100.00

4.03

4.21

2.92

2.21

2.915.07

4.06

4.94

4.71

%

3.64

3.96

2.53

4.00

3.59

2.57

2.26

2.17

6.90

Weight

2.28

4.31

5.33

2.77

3.96

4.46

3.47

6.74

1.31 1 3.23

NOTE: Weights are from random effects analysis

Overall (I-squared = 51.5%, p = 0.001)

Lv W (2002)

Zienolddiny S (2008)Yoon KA (2008)

Chevrier I (2003)

Park JH (2006)

Schabath MB (2002)Lu W (2002)

Kantarci OH (2002)

London SJ (1) (1997)

Larsen JE (1) (2006)Larsen JE (2) (2006)

Chan EC (2005)

Yang M (2007)

Feyler A (2002)

Arslan S (2011)

London SJ (2) (1997)

Wu X (2003)Cajas-Salazar N (2003)

Xu LL (2002)

Dally H (2002)

Misra RR (2001)

Klinchid J (2009)

Zhang T (2007)

Le Marchand L (2) (2000)

Liu G (2004)

Cascorbi I (2000)

IDStudy

Le Marchand L (1) (2000)

0.89 (0.81, 0.98)

0.65 (0.45, 0.93)

1.09 (0.78, 1.53)0.84 (0.51, 1.41)

1.07 (0.75, 1.53)

1.05 (0.74, 1.48)

0.68 (0.51, 0.91)0.65 (0.45, 0.93)

0.86 (0.62, 1.19)

0.83 (0.58, 1.19)

1.03 (0.76, 1.39)1.01 (0.78, 1.32)

1.89 (1.06, 3.36)

0.74 (0.49, 1.10)

0.67 (0.43, 1.05)

0.60 (0.38, 0.96)

1.19 (0.80, 1.78)

0.52 (0.30, 0.91)0.95 (0.56, 1.59)

1.05 (0.88, 1.25)

0.82 (0.62, 1.08)

1.27 (0.92, 1.76)

1.17 (0.61, 2.24)

1.15 (0.68, 1.95)

0.68 (0.39, 1.20)

1.12 (0.94, 1.35)

0.58 (0.39, 0.86)

OR (95% CI)

0.67 (0.42, 1.07)

100.00

3.88

4.142.58

3.93

4.05

4.753.88

4.33

3.93

4.605.14

2.18

3.48

3.03

2.94

3.47

2.312.53

6.39

4.91

4.30

1.81

2.49

2.24

6.27

3.54

Weight%

2.89

0.89 (0.81, 0.98)

0.65 (0.45, 0.93)

1.09 (0.78, 1.53)0.84 (0.51, 1.41)

1.07 (0.75, 1.53)

1.05 (0.74, 1.48)

0.68 (0.51, 0.91)0.65 (0.45, 0.93)

0.86 (0.62, 1.19)

0.83 (0.58, 1.19)

1.03 (0.76, 1.39)1.01 (0.78, 1.32)

1.89 (1.06, 3.36)

0.74 (0.49, 1.10)

0.67 (0.43, 1.05)

0.60 (0.38, 0.96)

1.19 (0.80, 1.78)

0.52 (0.30, 0.91)0.95 (0.56, 1.59)

1.05 (0.88, 1.25)

0.82 (0.62, 1.08)

1.27 (0.92, 1.76)

1.17 (0.61, 2.24)

1.15 (0.68, 1.95)

0.68 (0.39, 1.20)

1.12 (0.94, 1.35)

0.58 (0.39, 0.86)

OR (95% CI)

0.67 (0.42, 1.07)

100.00

3.88

4.142.58

3.93

4.05

4.753.88

4.33

3.93

4.605.14

2.18

3.48

3.03

2.94

3.47

2.312.53

6.39

4.91

4.30

1.81

2.49

2.24

6.27

3.54

Weight%

2.89

1.298 1 3.36

a

b

c

Fig. 1 Forest plot analyses forthe association between the MPOG463A polymorphism and thelung cancer risk. a Avs. G. b GAvs. GG. c AA + GAvs. GG

Tumor Biol. (2014) 35:821–829 825

case–control studies, under the following contrast models (Avs. G, OR=0.89, 95 % CI=0.79–0.99, POR=0.041; GA vs.GG, OR=0.87, 95 % CI=0.77–0.99, POR=0.034; AA+GAvs. GG, OR=0.87, 95 % CI=0.77–0.98, POR=0.028)(Table 2).

Stratified analysis by smoking status

Smokers carrying the AA + GA genotype were less likely todevelop lung cancer, whereas no significant correlation wasobserved in other genetic models (AA + GA vs. GG, OR=0.83, 95 % CI=0.70–0.99, POR=0.043) (Table 2). Besides,the MPO G463A polymorphism exerted no effect on the lungcancer development in nonsmokers (Table 2).

Stratified analysis by histology types

No significant relationship was identified between the MPOG463A polymorphism and the risk of lung adenocarcinomaand squamous cell carcinoma (Table 2).

Heterogeneity analysis and publication bias risk

The between-study heterogeneity was significant in contrastmodels of among total studies (A vs. G, I2=60.2, PH<0.001;AA vs. GG, I2=50.3, PH=0.002; GA vs. GG, I2=47.4, PH=0.004; AA + GA vs. GG, I2=51.5, PH=0.001; AA vs. GG +GA, I2=48.5, PH=0.003) (Table 2). Stratified analysis did notidentify the main source of between-study heterogeneity.Begg's funnel plot and Egger's test provided no evidence ofpublication bias risk in our study (Fig. 2).

Discussion

Available published data support that there are significantvariations in individual susceptibility to lung cancer [44, 45].To the best of our knowledge, genetic predispositions arerelated to the single-nucleotide polymorphisms of many met-abolic enzymes including the MPO G463A gene, which wasinvolved in the metabolism of procarcinogens [12, 34]. Theaim of our study was to estimate the role of MPO G463Apolymorphism in lung carcinogenesis by performing a com-prehensive meta-analysis. Totally, 24 individual studies with8,313 cases and 8,728 controls were retrieved by a literaturesearch in the PubMed, Embase, and Wanfang databases. Thepooled analysis suggested that the MPO G463A polymor-phism played a protective role in the development of lungcancer, particularly in populations of Asians and Caucasians.Similar findings were observed among the smokers andpopulation-based case–control studies by conducting strati-fied analyses by smoking status and source of controls. TheMPOG463A polymorphism seemed to exert no effect on lungadenocarcinoma and squamous cell carcinoma.

Contrary to the findings in our study, a recent meta-analysisbased on 22 published case–control studies including 7,520patients and 8,600 controls revealed that the MPO G463Apolymorphismmay not be a risk factor for lung cancer [46]. Intheir stratified analyses by ethnicity, source of controls, andsmoking status, significant association of the MPO G463Apolymorphism with lung cancer risk was also not observed[46]. In addition, they did not carry out stratified analysis byhistological types of lung cancer, age, sex, and other con-founding factors. It was worth noting that the sample size ofall included case–control studies may be not sufficient enoughto identify a minor gene susceptibility to lung cancer. Thepresent meta-analysis provided a strong evidence for the

Begg's funnel plot with pseudo 95% confidence limits

logo

r

s.e. of: logor

0 .1 .2 .3

-1

-.5

0

.5

Fig. 2 Funnel plot analysis forthe publication bias risk (for GAvs. GG, PEgger=0.152)

826 Tumor Biol. (2014) 35:821–829

protective role of MPO G463A polymorphism in the lungcancer development, although no significant correlation wasfound when stratifying analysis in lung adenocarcinoma andsquamous cell carcinoma.

The MPO G463A variant genotypes may contributeto the lung carcinogenesis in combination with certainenvironmental factors, for example, smoking [47]. Aninteraction between the MPO G463A polymorphism andcigarette smoking has been implicated in the develop-ment of lung cancer [27, 28, 47, 48]. Lu et al. demon-strated that heavy smokers (≥26 pack years) carrying theMPO G463A variant genotype were less likely to de-velop lung cancer than light smokers (<26 pack years)with the variant genotype [27], which suggested that theassociation between the MPO G463A polymorphismand the lung cancer risk could be altered by the dura-tion of smoking. However, such association was notsignificant in the risk of lung adenocarcinoma, exceptthe lung squamous cell carcinoma [27]. Schabath et al.found a protective role of the AA + GA-combinedgenotype in ever smokers rather than never smokers[28]. Due to insufficient published studies, we did notestimate the effect of smoking on different histologicaltypes of lung cancer, such as squamous cell carcinomaand adenocarcinoma. Nevertheless, the stratified analysisby smoking status showed that smokers carrying the AA+ GA-combined genotype were at a reduced risk oflung cancer (AA + GA vs. GG, OR=0.83, 95 % CI=0.70–0.99, POR=0.043). Besides cigarette smoking,more epidemiological studies should investigate themodifying effect of other environmental factors suchas air pollution, radon radiation, and chronic airwayinflammation on the lung cancer pathogenesis [49, 50].

The MPO polymorphisms may interplay with othersusceptible genes, and they play vital roles in carcino-genesis, such as cancers of the esophagus, prostate, andbreast [51–54]. A combination of the glutathione S -transferase P1, MPO, and cytochrome P450 1A1single-nucleotide polymorphisms was suggested to mod-ify the susceptibility to lung cancer, indicating a poten-tial role of gene–gene interaction in lung carcinogenesis[39]. Moreover, the susceptibility of MPO G463A tolung cancer varied by age and sex. The genotype dis-tribution of MPO G463A between the lung cancersmokers and the controls differed with statistical signif-icance; however, this difference was not statisticallysignificant for nonsmokers [43]. A number of studieshave suggested that women have a higher risk of lungcancer than men, although they were exposed to thesame level of smoking [55–57]. A previous study pro-vided the evidence that the MPO variant genotypeswere significantly associated with a lower risk of lungcancer among men only, but not women [58]. The study

by Yoon et al. supported the evidence that the MPOG463A polymorphism did not significantly correlatewith the risk of lung cancer in never-smoking Koreanwomen [41]. Park and colleagues observed no evidenceof modifying effect by age and gender in the suscepti-bility of MPO G463A polymorphism to lung cancer[37]. The contradictory findings across publicationsmay be attributed to diverse ethnicities, source of controls,as well as complicated genetic backgrounds. Up till now, littlehas been known about the effect of MPO G463A variantgenotypes on lung cancer pathogenesis between men andwomen in different ages. We failed to perform stratified anal-ysis by sex and age to assess the relationship of mutant MPOG463Awith the lung cancer risk, and in that, information wasnot all available in all included studies regarding the effects ofgender and age. Given the influence of age and sex, the preciseassociation of MPO G463A polymorphism and the lung can-cer risk should be further elucidated in more subsequentstudies.

The frequency of MPO G463A alleles and genotypesvaries in different ethnic groups. The MPO G463A polymor-phism was confirmed to afford a protective effect on the lungcancer risk in Caucasians, especially among small cell lungcancer patients [26]. Caucasians with the AAvariant genotypeof MPO G463A were at reduced risk of lung cancer, while alesser reduction in lung cancer risk was observed among theAfricans carrying this genotype [20]. Zhang et al. reported thatno appreciable correlation was identified in the susceptibilityof MPOG463A polymorphism to lung cancer in Chinese Hanpopulation [38]. However, Wu et al. found that the carrierswith the variant allele of MPO G463Awere at decreased riskof lung cancer in a Chinese population [31]. To diminish theimpact of confounding factor, namely, ethnicity, we carriedout stratified analysis in the Asians and Caucasians, exceptfrom the Africans, because only one individual case–controlstudy was conducted among Africans [20].

The current meta-analysis was based on an unadjustedestimate for the risk for lung cancer due to a lack of adjustedevaluation by age, sex, tobacco smoking, alcohol consump-tion, education, income of subjects, and so on. Future studieswith a large sample size may make the adjusted analysis forthe relationship between MPO G463A gene and lung cancerrisk.

In summary, our study suggests that the polymorphism ofMPO G463A is a protective factor for lung cancer, particular-ly in Asians, Caucasians, and smokers. Nevertheless, morestudies with high quality are needed to further elucidate theeffect of MPO G463A mutation on lung carcinogenesis, con-sidering the potential roles of gene–gene and gene–environ-ment interactions. Moreover, adjusted estimates by age, sex,and other confounding factors are recommended when inves-tigating the susceptibility of MPO G463A polymorphism tolung cancer.

Tumor Biol. (2014) 35:821–829 827

Conflicts of interest None.

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