Review Article Genetic Epidemiology, Hematological and Clinical Features...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 803487 10 pageshttpdxdoiorg1011552013803487

Review ArticleGenetic Epidemiology Hematological and Clinical Features ofHemoglobinopathies in Iran

Zohreh Rahimi12

1 Medical Biology Research Center Kermanshah University of Medical Sciences Daneshgah AvenuePO Box 67148-69914 Kermanshah Iran

2Department of Biochemistry Medical School Kermanshah University of Medical Sciences Daneshgah AvenuePO Box 67148-69914 Kermanshah Iran

Correspondence should be addressed to Zohreh Rahimi rahimizusyahoocom

Received 6 April 2013 Accepted 3 June 2013

Academic Editor Bipin Savani

Copyright copy 2013 Zohreh Rahimi This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

There is large variation in the molecular genetics and clinical features of hemoglobinopathies in Iran Studying structural variantsof hemoglobin demonstrated that the 120573-chain variants of hemoglobin S andD-Punjab aremore prevalent in the Fars (southwesternIran) and Kermanshah (western Iran) provinces respectively Also 120572-chain variants of Hb Q-Iran and Hb Setif are prevalent inwestern Iran The molecular basis and clinical severity of thalassemias are extremely heterogenous among Iranians due to thepresence of multiethnic groups in the country 120573-Thalassemia is more prevalent in northern and southern Iran Among 52 different120573-thalassemia mutations that have been identified among Iranian populations IVSII-1 GA is the most frequent mutation in mostparts of the country The presence of IVS I-5 GC mutation with high frequency in southeastern Iran might reflect gene flowfrom neighboring countries A wide spectrum of 120572-thalassemia alleles has been detected among Iranians with minus12057237 kb as the mostprevalent 120572-thalassemia mutation The prevention program of thalassemia birth in Iran has reduced the birth rate of homozygous120573-thalassemia since the implementation of the program in 1997 In this review genetic epidemiology clinical and hematologicalaspects of hemoglobinopathies and the prevention programs of 120573-thalassemia in Iran will be discussed

1 Introduction

Inherited disorders of hemoglobin hemoglobinopathies arethe most common monogenic diseases They are a group ofautosomal recessive disorders that are classified to two maingroups of thalassemia syndromes (120572- and 120573-thalassemia)and structural variants of hemoglobins [1] The presenceof a structural variant along with reduced synthesis ofhemoglobin is observed in Hb E [2] The wide variationin the clinical manifestation of hemoglobin disorders couldbe attributed to the influence of various genetic modi-fiers and environmental factors Heterogenous distributionof the disease and the presence of high variation in thephenotypic manifestation of a specific mutation are majorproblems with the development of programs for the con-trol of the hemoglobinopathies [1] High frequency of thehemoglobinopathies in some populations especially in manytropical countries reflects heterozygote advantage againstsevere malaria [1] Also consanguineous marriage plays an

important role in high frequency of these disorders [3]Iran a country with medium malaria endemicity and highrates of consanguineous marriage consisted of different eth-nic groups with various prevalence and clinical feature ofhemoglobinopathies So the knowledge of genetic epidemi-ology of hemoglobinopathies in the country will be of valu-able help in the development of successful prevention pro-grams and better diagnosis and management of hemoglobindisorders in Iran

2 Malaria and Hemoglobinopathies

Malaria disease is transmitted by anopheline mosquitoesThis disease is highly distributed in tropical and subtropi-cal regions Malaria hypothesis suggested by Haldane wasbased on the high carrier frequency of hemoglobinopathiesin areas with malaria endemicity a phenomenon protectscarriers against malaria and might be due to the balanced

2 BioMed Research International

polymorphism in human populations [4] Epidemiologicin vitro and in vivo studies support association betweenstructural variants of Hb S Hb C and Hb E as well as 120572-and 120573-thalassemia with areas of prevalence of Plasmodiumfalciparum [5]

The Hb S variant decreases the risk of infection by P fal-ciparum The mechanism of red blood cells (RBC) resistancein sickle cell trait (AS) individuals could be due to the lack ofparasite development and accelerating Hb S polymerizationin lowO

2tension andhigher rates of phagocytosis of parasite-

infected sickle erythrocyte by host immune cells [4 5] TheHb AS protects against all forms of malaria by elimination ofparasites in 90 of Hb S cell populations In Hb S carriers theselection occurs at the cost of the loss of homozygotes fromsickle cell disease [4 6]

The selective advantage of Hb C is greater in homozygousstate (90) than in Hb AC carriers (30) [6]

The protection of 120573-thalassemia patients against malariais due to delay of switching from fetal to adult hemoglobinresulting in higher level of intracellular Hb F The Hb F ismore stable and stronger than Hb A and is partially resistantto digestion by proteolytic machine of parasite So Hb Fcontaining red cells are inadequate hosts for P falciparumand this hemoglobin protects the host from the lethality ofmalaria [5] Also the presence of higher levels of serumantibodies bound to 120573-thalassemic erythrocytes is the othermechanism provides the protection against malaria in thesepatients [4]120572-Thalassemia is very prevalent in malaria endemic regi-

ons which protects against severe forms of P falciparuminfectionThe infected erythrocytes of 120572-thalassemia patientshave high levels of antibodies on their surface that promoteantiparasite effects [4] The protection of 120572+-thalassemiaagainst malaria might be due to higher susceptibility of hom-ozygotes tomalaria in early life that immunize these individu-als and make them resistance to malaria later [7] The prote-ctive effect of 120572-thalassemia is specific to severe malaria [6]

Iran as an eastern Mediterranean country with mediummalaria endemicity [8] started the program of malaria eradi-cation in 1956 Later in 1980 the program changed to malariacontrol program Now this disease is mostly restricted tothree southeastern provinces of Sistan-BaluchestanHormoz-gan and Kerman [9] According toWHOmalaria report Iranis classified in the preelimination stage ofmalaria [10] Due toheterozygote advantage against P falciparum malaria thereis a high incidence of the 120573-thalassemia in Iran especiallyin northern and southern Iran as the ten provinces withhigh prevalence of 120573-thalassaemia are Gilan HormozganKhuzestan Kohgiluyeh-Boyer-Ahmad Fars Bushehr Sistan-Baluchestan Kerman and Isfahan in northern and southernIran [11 12] The Sistan-Balouchestan province that is themost prevalent area for malaria comprises 42ndash60 of totalmalaria cases of Iran Majority of infected cases (85) withmalaria were due to P falciparum [13] Isfahan provincelocated in central Iran has been classified as the sixth moreprevalent province for malaria after Sistan-BalouchestanHormozgan Kerman Fars and Tehran provinces [14]

The gene frequency of 120573-thalassaemia has been estimatedto be 00174 with over 225 million carriers [15] An overall

rate of consanguineous marriage (majority first-cousin mar-riages) is 386 (ranges from 16 to 47) in Iran [15]

3 Structural Variants

31 Hemoglobin S The hemoglobin (Hb) S that results fromglutamic acidrarr valine amino acid substitution at position6 of 120573-chain is the most clinically important structuralvariant of hemoglobin with highest frequency in AfricaSaudi Arabia and India Sickle cell disease (SCD) resultsfrom the homozygous state of the mutation or a compoundheterozygous state with one of structural variants of Hb D-Punjab Hb O-Arab Hb C or 120573-thalassemia mutation in theother 120573-genes [16 17]

First report of clinical and hematological features of sicklecell anemia in southern Iran demonstrated the high level ofHb F (18) and mild clinical course of the disease in Iranianpatients [18] The prevalence of sickle cell trait and sickle cellanemia in southern Iran has been estimated to be around 143and 01 respectively [19] In central Iran (southeast Isfahan)sickle cell trait was reported with a frequency of 833 [20]In contrast in western Iran the lowest frequency for thishemoglobin variant compared to structural variants of HbD-Punjab Hb Q-Iran and Hb Setif was reported [21]

32 Hb D-Punjab Hb D-Punjab (D-Los Angeles) is char-acterized by substitution of glutamine for glutamic acid atposition of 121 of 120573-globin chain [22] The presence of HbD-Punjab in combination with an 120572-chain variant (Hb O-Indonesia) in an Iranian patient was reported 37 years agoby Rahbar et al [23] The case had no hemolytic disordersand clinical symptoms Subsequent report indicated that inKurdish population from western Iran Hb D-Punjab was themost prevalent structural 120573-globin variant [22]

Hb D-Punjab was detected as the second prevalentstructural variant in southern province of Khuzestan [24]Mild clinical presentation of this variant in homozygous andcombined heterozygous state with a 1205730-thalassemic mutationand also with concomitant presence of 120572- and 1205730-thalassemiamutations have been indicated [22] Benign feature of Hb D-Punjab was confirmed by two separate reports of concomi-tant presence of this structural variant with 120573-thalassemiamutation of IVSII-1GA that produced aminor120573-thalassemiapicture [25 26]

33 HbQ-Iran Single nucleotidemutations in 1205721 or 1205722 genesproduce abnormal 120572-chain hemoglobins Hb Q disordersincluding Hb Q-Iran [12057275 (EF4) AsprarrHis] Hb Q-Thailand[12057274 (EF3) AsprarrHis] and Hb Q-India [12057264 (E13) AsprarrHis] are important Hb variants All of these hemoglobinsare slow moving variants that migrate at the electrophoreticposition of Hb S at alkaline pH [27 28] In carriers of Hb Q-Iran this hemoglobin has a level of 17ndash19 and hematologicalindices are normal [29] In recent studies from Kurdishpopulation of western Iran this Hb variant was the secondprevalent structural variant with a level of 142ndash293 andin carriers of this hemoglobin hematological indices werenormal [21 29]

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34 Hb Setif Hb Setif [12057294 (G1) AsprarrTyr] is an 120572-chainHb variant with electrophoretic mobility similar to Hb Sat alkaline pH Hb Setif is much less soluble than Hb Aand induces pseudosickling of the red cells in vitro Thishemoglobin presents in a low percent (12ndash17) Hb Setif hasbeen found in Algeria Iran Lebanon Saudi Arabia TurkeyItalyMalta and CyprusThis 120572-chain variant was found to bethird prevalent structural variant among Kurdish populationfrom western Iran with a level of 108ndash271 and normalhematological indices in carriers of the hemoglobin [29]

35 Epistatic Modifiers and Structural Variants

351 Hb S The 120573S mutation has been found to be inlinkage disequilibrium with five distinct typical (common)120573-globin gene cluster haplotypes Four of these haplotypesare known as African haplotypes (Bantu Benin Senegaland Cameroon) the fifth is the Arab-Indian haplotypewhich was originally described in the eastern oases of SaudiArabia and among the tribal Adivasi population of India[30] In Iran genetic studies and determination of haplotypebackground of 120573S gene for the first time were conducted incentral Iran which indicated that the 120573S gene was in linkagedisequilibrium with the Arab-Indian haplotype in this area[20] Subsequently in southwestern Iran the association of120573S gene with Arab-Indian haplotype was reported [31] Mildclinical presentation of sickle cell anemia in southwesternIran has been demonstrated with high level of Hb F and theelevation ratio of G120574 A120574 chains in sickle cell anemia patientsthat was attributed to the presence of Xmn I polymorphicsite associated with Arab-Indian haplotype [31 32] Moreanalysis of 120573S gene from different provinces of southwesternIran demonstrated that the most prevalent haplotype invarious ethnic groups (Fars and Arabs) was the Arab-Indianhaplotype [30] However around 33 of 120573S genes werecorrelated with African haplotype These findings providedan evidence of multicentric origin of 120573S gene in southwesternIranThe prevalence ofminus12057237 kb mutation among SCDpatientsfrom southwestern Iran was around 37 The beneficialeffect of the presence of 120572+-thalassemia in SCD patients ofsouthwestern Iran was appeared in lower levels of MCHand MCV [32] In western Iran the 120573S gene was in linkageequilibrium with Benin haplotype [21]

352 Hb D-Punjab Molecular genetic studies indicated anassociation between 120573D-Punjab gene with haplotype I andits unicentric origin in western Iran [22] However in twosouthern provinces of Fars and Hormozgan four haplotypebackgrounds for 120573D-Punjab gene with the most prevalenthaplotype I (675) have been observed [33]

353 Hb Q-Iran Higher expression of HbQ-Iran with lowerlevels of MCV in carriers of this hemoglobin was observedwith concomitant presence of this variant with minus12057237 kb muta-tion [21] It has been suggested that Hb Q-Iran is a benignstructural variant of Hb which in combination with a 1205730-thalassemia mutation and in the presence of 120572+-thalassemia

produces only a minor 120573-thalassemia picture with moderateanemia and elevation of Hb F [34]

4 Thalassemia

Thalassaemias are characterized by decrease or absenceproduction of 120572- or120573-globin chains which result in twomaintypes of 120572- or 120573-thalassemia [35] More than 200 differenttypes of deletional and nondeletional mutations in 120572- or 120573-globin genes have been detected with diverse clinical man-ifestations ranging from asymptomatic to profound fatalanemias in utero [36]

41 120573-Thalassemia 120573-Thalassemia has a high prevalence(around 10) in north close to the Caspian sea and Southof Iran close to the Persian Gulf The prevalence of 120573-thalassemia alleles in most parts of the country has beenestimated to be 4ndash8 [37 38] Overall there are 20000homozygote and 3750000 carriers of 120573-thalassaemia in Iran[39]

Finding 52 different mutations among Iranians and thepresence of different mutations in 21 of consanguineouscouples suggest the heterogeneous picture of 120573-thalassaemiamutations among Iranian populations [15] So many studiesin various parts of Iran have been performed to establishthe spectrum of 120573-thalassemia mutations to help the prenataldiagnosis

411 Southern Iran In reports from three ethnic groups ofSouthern provinces of Fars Hormozgan and Khuzestan dif-ferent spectrum and prevalence of 120573-thalassemia mutationswere obtained [24 37 40ndash42] In the Fars province (with eth-nic background of Fars) IVS II-1 GA and IVS I-6 TCwere themost prevalent 120573-thalassemic mutations with the frequenciesof 31 and 15 respectively among 10 different mutationsthat were found in 26 studied chromosomes that suggesteda genetic admixture and migrations for the presence of highnumber of 120573-thalassemic mutations in this area [40] Secondand third reports from this area confirmed the presence ofIVS II-1 GA as the most prevalent 120573-thalassemic mutationthat was associated with Xmn I polymorphic site [37 41]However in other southern province of Hormozgan (withvarious ethnic groups of Fars Arab and Balouch) neighbor-ing the Fars province the IVS I-5 GC with a frequency of69was themost prevalentmutation followed by the IVS II-1GA (96) In contrast with other provinces of Iran no IVSI-110 GA or IVS I-1 GA mutations were found in this areaAlso the severe phenotype of patients homozygous for theIVS II-745 CG mutation was linked in cis to the 51015840UTR +20CT transition [42] In more recent study from Hormozganprovince among 224120573-thalassaemia carriersmostly with Farsorigin (98) the IVS I-5 GC mutation with a frequency of71 was the most prevalent mutation followed by IVS II-1GA (12) [12] In this province due to malaria selection andhigh rates of consanguineous marriages hemoglobinopathiesare common [12] In another southern province of Khuzestanwith Arab ethnic background three most commonmutationsincluding CD 3637-T IVS-II-1 GA and IVS-I-110 GA at afrequency of 205 200 and 142 respectively were detected


[24]Thepicture of120573-thalassaemiamutations in this provinceis heterogenic with detecting 42 different types of mutations[24]

412 Northern Iran In three northern provinces of Mazan-daran Gilan and Golestan IVS-II-1 G A with a frequencyof 50 was the highest prevalent mutation followed by CD30 GC (77) The CD 8 minusAA CD 222324 ndashAAGTTGGand IVS-I-5 GC were the other common mutations in thearea [43] Similarly in other studies from these northernprovinces the IVS-II-1 GA was the most prevalent mutation(561) and the CD 30 GC (81) was the second prevalentmutation However CD 89 +G (61) CD 222324 ndashAAGTTGG (3) IVS-I-110 GA (25) IVS-I-5 GC (23)and IVS-II-745CG (23)were the other commonmutations[44] High prevalence of IVS-II-1 GA in northern Irancompared to other parts of Iran might be attributed tohigh rates of consanguineous marriages in this area [44] Insubsequent study fromMazandaran the frequency of IVS-II-1 GA mutation as the most prevalent mutation was 61 [45]and the CD 30 GC with a frequency of 75 was the secondprevalent mutation Also in provinces of East Azerbaijan andArdabil northwestern the most frequent mutations in orderof frequencies were IVS-II-1 GA (21) IVS-I-110 GA (18)CD 89 +G (145) CD 8 minusAA (8) and IVS-I-1 GA (75)[46]

In northeastern province of Khorasan in a small subset ofchromosomes theCD89 +Gwas themost frequentmutation(625) and each of the three mutations of IVS-II-1 GA3637 ndashT and CD 39 CT had a frequency of 125 [43]

413 Western Iran The spectrum of 120573-thalassemia muta-tions in western Iran provinces of Kermanshah (mostlyKurds) Kurdistan (with Kurdish ethnic background) Lores-tan (mostly Lors) Ilam (mostly Kurds) and Hamadan(mostly Fars) were identified [43 47ndash49] In the Kermanshahprovince twenty different mutations were identified thatamong them around 81 were of 1205730 type mutation Fourmost common mutations in this part of Iran were IVSII-1GA (3297) CD89 +G (1351) IVSI-110 (GA) (838)and CD 3637 minusT (784) [47] Test of heterogeneity betweendifferent Iranian populations indicated that Kermanshahpopulation is significantly different from the population ofsouthern Iran (119875 lt 0004) degree of freedom (df = 7) butconsidering the most frequent mutations the spectrum of 120573-thalassemia mutations in Kermanshah is similar to peoplefrom Lorestan Ardabil East Azerbaijan Gilan MazandaranGolestan Tehran and Isfahan [47]

The spectrum and frequency of 120573-thalassemia mutationsin Kurdistan province have been found to be similar to theKermanshah province In the Kurdistan province IVS-II-1GA was the most frequent comprising 35 of all mutationsOther common mutations were CD 89 +G (157) IVS-I-1GA (8) CD 5 minusCT (67) CD 8 minusAA (67) and IVS-I-110 GA (6) [48] In the Lorestan province CD 3637 minusTmutation with a frequency of 338 was the most commonmutation This mutation has been detected among KurdishJews [43] The other most frequent mutations were IVS-II-1GA IVS-I-110 GA and CD 89 +G with the frequencies of

277 115 and 108 respectively [49] In two other westernprovinces of Hamadan and Ilam IVSII-1 GA (294) wasthe most prevalent mutation and IVSI-110 GA and CD 8minusAA were the second and third prevalent mutations withfrequencies of 196 and 117 [43]

414 Central Iran In a study from central provinces ofTehran Isfahan Yazd Markazi and Semnan the three mostcommon mutations were IVS-II-1 GA (28) CD 89 +G(117) and IVS-I-5 GC (93) [43] In a subsequent reportfrom the Isfahan province the presence of IVS-II-1 GA(205) as the most prevalent mutation was confirmedHowever the second prevalent mutation was IVS-I-5 GC(11) [50]

415 Southeastern Iran Thehigh frequency of120573-thalassemiaalleles in the Sistan-Balouchestan province could be attri-buted to the selection pressure by malaria and high ratesof consanguineous marriage among Balouch populationAround 90 of homozygous 120573-thalassemia patients of theprovince have ethnic background of Balouch [51]

In this province among Balouch population only IVS I-5 G C with an unusual frequency of 872 along with CD89 +G with a frequency of 4 constituted about 91 of120573-thalassemia mutations The IVS I-5 GC has been foundas the most prevalent mutation among Sindh and Balouch-estan provinces of Pakistan bordering Sistan-Balouchestanprovince of Iran [51] Also in southeastern province ofKerman IVS I-5 GC was detected to be the high prevalent 120573-thalassemic mutation (662) followed in order of frequencyby IVS II-1 GA (6) and CD 89 +G (49) [52]

The spectrumof120573-thalassemiamutations in various partsof Iran indicating the IVSII-1 GA as the prevalent mutationin most part of Iran with the highest frequency in northernIran and decreased its frequency toward southern Iran whereIVS I-5 GC is the highest prevalent mutation The highfrequency of Mediterranean mutation IVSII-1 GA in Iranmight be due to an independent origin of this mutation orgenetic admixture The Balouchestan province of Pakistanis known for the highest frequency of IVSI-5 GC Thepresence of this mutation as the most prevalent mutation inSoutheastern Iranian province of Sistan-Balouchestan mightbe due to genetic admixture with the population of neighborcountry of Pakistan The same reason could explain thesimilar frequency of IVS I-5 GC (69) between southernIranian province of Hormozgan and the southern neighborof United Arab Emirates (66) [43]

416 EpistaticModifiers and120573-Thalassemia Genetic variantsthat results in differences in disease phenotype are knownas modifier genes [53] These modifiers include the presenceof 120572-thalassemia (with reducing the globin chain imbalance)andor the presence of genetic determinants (with increasingthe production of Hb F) in adult life [53] High frequencyof 120572-thalassemia is observed in many populations withhigh prevalence of 120573-thalassemia [54] The presence of 120572-thalassemia in homozygous or compound heterozygous stateof 120573-thalassemia ameliorates the clinical presentation of


the disease due to the lower concentration of excess 120572-globinchains [55]

The IVS II-1 GA among Kurdish population of Kerman-shah province (western Iran) was strongly associated withhaplotype III [56] However this mutation in southern Iranwas mostly associated with haplotype I [57] A frequencyof 039 was obtained for the Xmn I polymorphic site in 120573-thalassemia major patients of western Iran associated withelevation in G120574-chain level and G120574 A120574 ratio and improvedclinical features [58] The increased numbers of 120574-chainsbind to excess 120572-globin chains produce Hb F and reduceglobin chain imbalance [55] Further the main molecularbasis of the 120573-thalassemia intermedia phenotype in Iraniancases was determined to be the coinheritance of a positiveXmn I polymorphism with 120573-globin mutations resulted inincrease Hb F production coinheritance of 120572-globin defectsand mild presentation of 120573-globin mutations [59] Also HS-111 and 31015840HS1 in the promoter region of 120574-globin gene in 120573-thalassemia intermedia patients were associated with highlevel of Hb F [60]

42 120572-Thalassemia The 120572-thalassemias are classified intothe 1205720-thalassemia with no synthesis of 120572-chains and 120572+-thalassemia with a reduction in synthesis of 120572-chains Theheterozygous andhomozygous1205720-thalassemia are designatedas minus120572120572 and minusminus respectively 120572+-Thalassemia in heterozy-gous and homozygous states is represented as minus120572120572120572 andminus120572minus120572 respectively [61] The severe 120572-thalassaemia muta-tions are restricted to Southeast Asia and some of theMediterranean islands The 120572+-thalassemia deletions are themost common forms of 120572-thalassemia with two major formsof minus12057237 kb and minus12057242 kb [1 61] Also more than 70 nondele-tional forms of 120572-thalassemia have been detected that mightbe coinherited with deletional mutations or other geneticmodifiers results in diverse genotypic andor phenotypicexpressions [36]

Identification of molecular spectrum of 120572-thalassemiain southern Iran (Hormozgan province) revealed the twocommon alleles ofminus12057237 kb (791) and120572minus5nt(minusTGAGG) (43) inthis area [62] Also the presence of minus12057237 kb single gene dele-tion as the most frequently 120572-chain variant in southwesternprovinces of Fars Khuzestan and Kohgiluyeh-Boyer-Ahmadwas confirmed [63 64]

In northern provinces of Mazandaran and Gilan 21 and16 different 120572-globin alleles respectively were found thatamong them minus12057237 kb with frequencies of 449 and 425respectively and 120572PolyA2(AATGAA) with frequencies of 182 and124 respectively were the most prevalent mutations in thisareaThe frequency of 120572minus5nt(minusTGAGG) was 65 inMazandaranand 71 in Gilan provinces [65 66]

In Kerman province from southeastern Iran the spectrumof 120572-thalassemia mutations indicated minus12057237 kb as the mostcommon mutation (838) followed by 120572CD19(minusG) (57) and120572minus5nt(minusTGAGG) (42) [67] In some cities of Kerman provincesuch as Jiroft and Kahnooj with malaria endemicity thehighest frequencies of 120572-thalassemia has been detected [67]

Overall studying 8 different geographic areas of Iranindicated the presence of 16 different 120572-globin mutations that

among them the minus12057237 kb mutation was found to be the mostfrequent 120572-thalassemia mutation comprising 602 of 120572-thalassemia alleles The highest frequency of this mutationwas observed in south (93) and the lowest frequency ofthe mutation was detected in central (539) Iran Nine ofthese mutations including minusMED minus12057242 kb 120572PolyA2(AATGAA)120572CS 120572minus5nt(minusTGAGG) minus120572205 120572PolyA1(AATAAG) 120572CD19 and 120572CD59reached to a polymorphic frequency (gt1) [68]

Hb H (minus minus 120572) is an unstable Hb resulting from deletionof three 120572-globin genes and has a mild-to-moderate severephenotype [69] This Hb forms intracellular precipitates thatresults in early cell death Hemolysis rather than ineffectiveerythropoiesis is the primary cause of anemia in Hb Hdisease Many patients require intermittent transfusions Theclinical severity is strongly influenced by the type ofmutationAmong Iranians the clinical diversity ofHbHdisease (similargenotypes with different phenotypes) has been reported [70]Deletions on chromosome 16 are responsible for 75 of HbH mutations and these deletions cause a milder form of thedisorder The remaining 25 of patients with Hb H diseasehave two deletions plus a point mutation or insertion in the120572-globin gene Nondeletional Hb H is often severe and likelyrequires transfusions Hemoglobin Constant Spring (Hb CS)is the most common nondeletional 120572-thalassemia mutationassociated with Hb H disease The gene frequency of Hb CSreaches to 8 in Southeast Asia The laboratory and clinicalcourse ofHbHCS disease aremore severe thanHbHdisease[71]

Studying molecular basis of Hb H disease in southwestIran indicated the presence of six genotypes associatedwith Hb H disease in the area including minus12057237 kbminusMEDminus12057237 kb120572T-Saudi120572 120572T-Saudi120572120572T-Saudi120572 120572CS120572minusMEDminusMED120572T-Turkish120572 and the atypical forms of Hb H diseaseminus12057237 kb120572CS120572 It has been suggested that the molecularbackground of Hb H disease in the southwest area of Iran ismore similar to theMediterranean type than to the SoutheastAsian [72]

A study conducted on patients with Hb H disease tofind the association between severity of phenotype accordingto Hb H genotype This study revealed a subset of Hb Hgenotypes including minusMED120572CS120572 minusMED120572PolyA2(AATGAA)120572and 120572CS120572120572CS120572 that was associated with a need for regular orirregular blood transfusions [73]

A map of Iran that depicts provinces with prevalenceof hemoglobinopathies is presented in Figure 1 Also thecommon types of hemoglobinopathies in different areas ofIran are demonstrated in Table 1

5 Prevention Programs

Due to large economic burden of treatment of120573-thalassaemiapatients for both affected individuals and national healthbudget a mandatory premarital screening program for 120573-thalassaemia was established [15] Preventing programs of 120573-thalassaemia in Iran aremore cost-effective than treatment ofthe disease [11]

In Iran public education screening and prenatal diag-nosis remarkably decreased the frequency of births of babies


Table 1 Common types of hemoglobinopathies in various parts of Iran

Area 120572-Chain variants 120573-Chain variants 120572-Thalassemia 120573-ThalassemiaNorthern Iran

Gilan minus12057237 kb (425) IVS II-1 G A (524)Mazandaran minus12057237 kb (449) IVS II-1 G A (621)Golestan IVS II-1 G A (333)

Northwestern IranEast Azerbaijan and Ardabil IVS II-1 G A (21)West Azerbaijan IVS II-1 G A (35)

Northeastern IranKhorasan CD 89 +G (625)

Central IranIsfahan Hb S IVS II-1 G A (205 and 28)

Southwestern IranFars Hb S 12057237 kb (717) IVS II-1 G A (24 31 and 478)

Khuzestan Hb SHb D-Punjab

minus12057237 kb (626) CD 3637 ndashT (205)IVS II-1 G A (20)

Western Iran

Kermanshah Hb Q-IranHb Setif

Hb D-Punjab IVS II-1 G A (33)

Kurdistan IVS II-1 G A (35)

Lorestan CD 3637 ndashT (338)IVS II-1 G A (277)

Southern IranHormozgan minus12057237 kb (791) IVS I-5 G C (69)

Southeastern IranSistan-Balouchestan IVS I-5 G C (872)Kerman minus12057237 kb (838) IVS I-5 G C (662)

Iranians (with different ethnicity) minus12057237 kb (602) IVS II-1 G A (34)

with severe forms of 120573-thalassaemia Thalassemia carrierscreening started from 1991 in Shiraz and then from 1995in all provinces of Iran with the aims to reduce the burdenof disorder by identifying those individuals at increased riskand to determine their reproductive risks and having anaffected child In 1997 the technical committee of prenataldiagnosis (PND) of 120573-thalassemia in the Ministry of HealthandMedical Educationwas established to define the standardprotocols for PND that resulted in a reduced rate of 120573-thalassemia incidence in the country [74] At first the onlymethod for prevention of 120573-thalassemia was premaritalscreening In 2001 the laws of the country were modifiedto permit abortion of affected fetuses [15] then from 2002the abortion before 16-week gestational age was possible[39] In southern and northern provinces of Iran where theprevalence of120573-thalassemia is high the results of this programhave been successful in decreasing the birth prevalenceof 120573-thalassemia However the incidence of this conditionhas not been eliminated yet [39] In this program it isrequired that every couple to be tested for 120573-thalassemiaby their red blood cell indices in order to receive a permit

for marriage registration If the results of the previous testwere conspicuous the levels of hemoglobin A

2and Hb

electrophoresis were also determined Couples who wereboth carriers received counseling For those who ignored therecommendation and decided to marry prenatal diagnosisand termination of pregnancy in case of an affected fetushave been offered [35 74] During this period the averageof high risk couple initially deciding not to marry was 90without detection of new cases of thalassemia [75] Also thetrend for prenatal diagnosis among at-risk couples of Sistan-Balouchestan significantly increased from 2002 to 2010 [51]Thalassemia screening program in Iran is a well-coordinatednational approach in which screening is integrated withservices for patients [76]

6 Conclusion

The molecular basis and clinical severity of 120572- and 120573-thalassemia are extremely heterogenous among Iraniansdue to the presence of multiethnic groups in the countryThe presence of Mediterranean 120573-thalassemic mutation of


Caspian Sea

Persian Gulf

Oman Sea

GolestanMazandaran

Gilan

TehranHamadan

Kermanshah

Kurdistan

Lorestan

Fars

Hormozgan

Bushehr

Kerman

Ardabil

Ilam

Khuzestan

Isfahan

Khorasan

West Azerbaijan

Sistan-Baluchestan

East Azerbaijan

Kohgiluyeh-Boyer-Ahmad

Figure 1 Map of Iran depicts provinces with prevalence of hemoglobinopathies

IVSII-1 GA with highest frequency in most parts of thecountry might be attributed to the independent origin of thismutation or genetic admixture However the presence of IVSI-5 GC mutation with high frequency in southeastern Iranmight reflect gene flow from neighboring countries A widespectrum of 120572-thalassemia alleles has been detected amongIranians with minus12057237 kb as the most prevalent 120572-thalassemiamutation There are few available studies on the frequencygenetic and clinical features of structural variants of Hb inIran All reports are from southwestern and western Iranindicated that the Hb S and Hb D-Punjab respectivelyhave been studied in details as the most prevalent structuralvariants in these parts of the country The prevention pro-gram of thalassemia birth in Iran by premarital screeningprenatal diagnosis and termination of pregnancies has beena successful policy in reducing birth rate of homozygous 120573-thalassemia and a large amount of medical expenses in Iransince the implementation of the program in 1997 However itis still more work to achieve zero 120573-thalassemic birth

Genetic Terms

HbD-Punjab (D-Los Angeles)

A structural variant of 120573-globin chain(CD 121 GlurarrGln)

Hb E A structural variant of 120573-globin chain(CD 26 Glurarr Lys) results in reducedsynthesis of 120573-globin chain

Hb Q-Iran A structural variant of 120572-globin chain(12057275 (EF4) AsprarrHis)

Hb Setif A structural variant of 120572-globin chain(12057294 (G1) AsprarrTyr)

Hb S A structural variant of 120573-globin chain(CD 6 GlurarrVal)

Hb H Deletion of three 120572-globin genes(minus minus 120572)

120572+-Thalassemia Reduced synthesis of 120572-globin chains1205720-Thalassemia Complete absence of synthesis of

120572-globin chains120573+-Thalassemia Reduced synthesis of 120573-globin chains1205730-Thalassemia Complete absence of synthesis of

120573-globin chains

Conflict of Interests

The author declares that there is no conflict of interests

References

[1] D J Weatherall ldquoCurrent trends in the diagnosis and manage-ment of haemoglobinopathiesrdquo Scandinavian Journal of Clinicaland Laboratory Investigation vol 67 no 1 pp 1ndash2 2007

[2] J M Old ldquoScreening and genetic diagnosis of haemoglo-binopathiesrdquo Scandinavian Journal of Clinical and LaboratoryInvestigation vol 67 no 1 pp 71ndash86 2007

[3] D J Weatherall ldquoThe inherited diseases of hemoglobin are anemerging global health burdenrdquo Blood vol 115 no 22 pp 4331ndash4336 2010

[4] C Lopez C Saravia A Gomez J Hoebeke and M A Patar-royo ldquoMechanisms of genetically-based resistance to malariardquoGene vol 467 no 1-2 pp 1ndash12 2010

[5] H L Shear L Grinberg J Gilman et al ldquoTransgenic miceexpressing human fetal globin are protected from malaria by anovel mechanismrdquo Blood vol 92 no 7 pp 2520ndash2526 1998

[6] T N Williams ldquoHuman red blood cell polymorphisms andmalariardquoCurrent Opinion inMicrobiology vol 9 no 4 pp 388ndash394 2006


[7] D Weatherall J Clegg and D Kwiatkowski ldquoThe role ofgenomics in studying genetic susceptibility to infectious dis-easerdquo Genome Research vol 7 no 10 pp 967ndash973 1997

[8] A Raeisi F Nikpoor M R Kahkha and L Faraji ldquoThe trend ofmalaria in Islamic Republic Iran from 2002 to 2007rdquo HakimResearch Journal vol 12 pp 35ndash41 2009 (Persian)

[9] B Farzinnia A Saghafipour andM R Abai ldquoMalaria situationand anopheline mosquitoes in Qom Province Central IranrdquoIranian Journal of Arthropod-Borne Diseases vol 4 no 2 pp61ndash67 2010

[10] A A Hanafi-Bojd H Vatandoost E Philip et al ldquoMalaria sit-uation analysis and stratification in Bandar Abbas CountySouthern Iran 2004ndash2008rdquo Iranian Journal of Arthropod-BorneDiseases vol 4 no 1 pp 31ndash41 2010

[11] N Ghotbi and T Tsukatani ldquoEvaluation of the national healthpolicy of thalassaemia screening the Islamic Republic of IranrdquoEasternMediterraneanHealth Journal vol 11 no 3 pp 308ndash3182005

[12] P Nikuei V Hadavi M Rajaei M Saberi F Hajizade and HNajmabadi ldquoPrenatal diagnosis for 120573-thalassemia major in theIranian Province of HormozganrdquoHemoglobin vol 32 no 6 pp539ndash545 2008

[13] A Ebrahimzadeh B Fouladi and A Fazaeli ldquoHigh rate ofdetection of mixed infections of Plasmodium vivax and Plas-modium falciparum in South-East of Iran using nested PCRrdquoParasitology International vol 56 no 1 pp 61ndash64 2007

[14] S Soleimanifard M Akbari M Sabetghadam and S SaberildquoMalaria situation in Isfahan in the last five yearsrdquo Journal ofIsfahan Medical School vol 29 pp 273ndash280 2011 (Persian)

[15] B S Strauss ldquoGenetic counseling for thalassemia in the IslamicRepublic of Iranrdquo Perspectives in Biology and Medicine vol 52no 3 pp 364ndash376 2009

[16] D J Weatherall J B Clegg D R Higgs andW G Wood ldquoThehemoglobinopathiesrdquo in The Metabolic and Molecular Basis ofInherited Disease C R Sriver A Beadet W S Sly and D ValleEds vol 3 pp 3417ndash3484 McGraw-Hill New York NY USA1995

[17] Z Rahimi and A Parsian ldquoSickle cell disease and venousthromboembolismrdquo Mediterranean Journal of Hematology andInfectious Diseases vol 3 Article ID e2011024 2011

[18] M Haghshenass F Ismail-Beigi J B Clegg and D J Weather-all ldquoMild sickle cell anaemia in Iran associated with high levelsof fetal haemoglobinrdquo Journal of Medical Genetics vol 14 no 3pp 168ndash171 1977

[19] F Habibzadeh M Yadollahie M Ayatollahie and M Hagh-shenass ldquoThe prevalence of sickle cell syndrome in South ofIranrdquo Iranian Journal of Medical Sciences vol 24 pp 32ndash341999

[20] S Rahgozar A A Poorfathollah A R Moafi and J M Oldldquo120573Sgene in Central Iran is in linkage disequilibrium with theIndian-Arab haplotyperdquo The American Journal of Hematologyvol 65 no 3 pp 192ndash195 2000

[21] Z Rahimi AMuniz andHMozafari ldquoAbnormal hemoglobinsamong Kurdish population ofWestern Iran Hematological andmolecular featuresrdquoMolecular Biology Reports vol 37 no 1 pp51ndash57 2010

[22] Z Rahimi R Akramipour R L Nagel A S Ahmadi A Meratand F Bahrehmand ldquoThe 120573-globin gene haplotypes associatedwith Hb D-Los Angeles [120573121(GH4)GlurarrGln] in WesternIranrdquo Hemoglobin vol 30 no 1 pp 39ndash44 2006

[23] S Rahbar G Nowzari and M Poosti ldquoA double heterozy-gous hemoglobin hemoglobin O(Indonesia) and hemoglobinD(Punjab) in an individualrdquo The American Journal of ClinicalPathology vol 64 no 3 pp 416ndash420 1975

[24] H Galehdari B Salehi S Azmoun B Keikhaei K M Zan-dian andM Pedram ldquoComprehensive spectrumof the120573-thala-ssemia mutations in Khuzestan Southwest Iranrdquo Hemoglobinvol 34 no 5 pp 461ndash468 2010

[25] Z Rahimi R Akramipour S Korani and R L Nagel ldquoHb D-punjab [120573 121 (GH4) GlurarrGln]1205730-thalassemia [IVSII1(GrarrA)] in two cases from an Iranian family first reportrdquo TheAmerican Journal of Hematology vol 81 no 4 pp 302ndash3032006

[26] M T Basmanj M Karimipoor A Amirian et al ldquoCo-inher-itance of hemoglobin D and 120573-thalassemia traits in three Ira-nian families clinical relevancerdquo Archives of Iranian Medicinevol 14 no 1 pp 61ndash63 2011

[27] P A Lorkin D Charlesworth H Lehmann S Rahbar STuchinda and L I Eng ldquoTwo haemoglobins Q 120572-74 (EF3)and 120572-75 (EF4) aspartic acidrarr histidinerdquoThe British Journal ofHaematology vol 19 no 1 pp 117ndash125 1970

[28] M Aksoy A Gurgey C Altay et al ldquoSome notes about Hb Q-India and Hb Q-Iranrdquo Hemoglobin vol 10 no 2 pp 215ndash2191986

[29] Z RahimiMRezaei R LNagel andAMuniz ldquoMolecular andhematologic analysis of hemoglobin Q-Iran and hemoglobinSetif in Iranian familiesrdquo Archives of Iranian Medicine vol 11no 4 pp 382ndash386 2008

[30] Z Rahimi A Merat N Gerard R Krishnamoorthy and RL Nagel ldquoImplications of the genetic epidemiology of globinhaplotypes linked to the sickle cell gene in Southern IranrdquoHuman Biology vol 78 no 6 pp 719ndash731 2006

[31] Z Rahimi M Karimi M Haghshenass and A Merat ldquo120573-globin gene cluster haplotypes in sickle cell patients fromSouth-west Iranrdquo The American Journal of Hematology vol 74 no 3pp 156ndash160 2003

[32] Z Rahimi A Vaisi-Raygani AMeratM Haghshenass andMRezaei ldquoLevel of hemoglobin F and 119866120574 gene expression in sicklecell disease and their association with haplotype and XmnIpolymorphic site in South of Iranrdquo Iranian Journal of MedicalSciences vol 32 no 4 pp 234ndash239 2007

[33] M Yavarian M Karimi F Paran C Neven C L Harteveldand P C Giordano ldquoMulti centric origin of Hb D-Punjab [120573121(GH4)GlurarrGln GAArarrCAA]rdquo Hemoglobin vol 33 no 6pp 399ndash405 2009

[34] Z Rahimi R Akramipour A Vaisi-Raygani R L Nagel andA Muniz ldquoAn Iranian child with HbQ-Iran [12057275 (EF4) AsprarrHis]minus12057237 kbIVSII1 GrarrA first reportrdquo Journal of PediatricHematologyOncology vol 29 no 9 pp 649ndash651 2007

[35] N E Cousens C L Gaff S A Metcalfe and M B DelatyckildquoCarrier screening for 120573-thalassaemia a review of internationalpracticerdquo European Journal of Human Genetics vol 18 no 10pp 1077ndash1083 2010

[36] E A Rachmilewitz and P J Giardina ldquoHow I treat thalassemiardquoBlood vol 118 no 13 pp 3479ndash3488 2011

[37] Z Rahimi A V Raygani A Merat et al ldquoThalassemic muta-tions in southern Iranrdquo Iranian Journal of Medical Sciences vol31 no 2 pp 70ndash73 2006

[38] A Valaei F Bayat A Kordafshari S Zeinali and M Karim-ipoor ldquoA novel polymorphism causes a different restrictionpattern by RsaI in the 120573-globin gene cluster application in


prenatal diagnosisrdquo Hemoglobin vol 33 no 6 pp 417ndash4212009

[39] M Karimi N Jamalian H Yarmohammadi A AskarnejadA Afrasiabi and A Hashemi ldquoPremarital screening for 120573-thalassaemia in Southern Iran options for improving theprogrammerdquo Journal of Medical Screening vol 14 no 2 pp 62ndash66 2007

[40] A Merat M Haghshenas Z M Pour et al ldquo120573-thalassemia inSouthwestern IranrdquoHemoglobin vol 17 no 5 pp 427ndash437 1993

[41] M Karimi H Yarmohammadi S Farjadian et al ldquo120573-thala-ssemia intermedia from Southern Iran IVS-II-1 (GrarrA) is theprevalent thalassemia intermedia allelerdquo Hemoglobin vol 26no 2 pp 147ndash154 2002

[42] M Yavarian C L Harteveld D Batelaan L F Bernini and P CGiordano ldquoMolecular spectrum of 120573-thalassemia in the IranianProvince of Hormozganrdquo Hemoglobin vol 25 no 1 pp 35ndash432001

[43] H Najmabadi R Karimi-Nejad S Sahebjam et al ldquoThe 120573-thalassemia mutation spectrum in the iranian populationrdquoHemoglobin vol 25 no 3 pp 285ndash296 2001

[44] P Derakhshandeh-Peykar H Akhavan-Niaki A Tamaddoni etal ldquoDistribution of 120573-thalassemia mutations in the NorthernProvinces of IranrdquoHemoglobin vol 31 no 3 pp 351ndash356 2007

[45] H Akhavan-Niaki P Derakhshandeh-Peykar A Banihashemiet al ldquoA comprehensive molecular characterization of 120573 tha-lassemia in a highly heterogeneous populationrdquo Blood CellsMolecules and Diseases vol 47 no 1 pp 29ndash32 2011

[46] M A H Feizi A A H Feizi N Pouladi M Haghi and PAzarfam ldquoMolecular spectrum of 120573-thalassemia mutations inNorthwestern Iranrdquo Hemoglobin vol 32 no 3 pp 255ndash2612008

[47] Z Rahimi A Muniz and A Parsian ldquoDetection of responsiblemutations for120573 thalassemia in theKermanshahProvince of Iranusing PCR-based techniquesrdquoMolecular Biology Reports vol 37no 1 pp 149ndash154 2010

[48] M Haghi S Khorshidi M A H Feizi N Pouladi and A A HFeizi ldquo120573-thalassemia mutations in the iranian kurdish popula-tion of kurdistan and west azerbaijan provincesrdquo Hemoglobinvol 33 no 2 pp 109ndash114 2009

[49] A A Kiani Y Mortazavi S Zeinali and Y Shirkhani ldquoThemolecular analysis of 120573-thalassemia mutations in LorestanProvince Iranrdquo Hemoglobin vol 31 no 3 pp 343ndash349 2007

[50] R Salehi C A Fisher P A Bignell G Eslami and J M OldldquoIdentification of three novel mutations [-41 (AgtC) codon 24(G) and IVS-I-109 (-T)] in a study of 120573-thalassemia alleles inthe Isfahan Region of Iranrdquo Hemoglobin vol 34 no 1 pp 115ndash120 2010

[51] E Miri-Moghaddam A Zadeh-Vakili Z Rouhani M NaderiP Eshghi and A K Feizabad ldquoMolecular basis and prenataldiagnosis of 120573-thalassemia among Balouch population in IranrdquoPrenatal Diagnosis vol 31 no 8 pp 788ndash791 2011

[52] N Saleh-Gohari and M R Bazrafshani ldquoDistribution of 120573-globin gene mutations in thalassemia minor population ofkerman province Iranrdquo Iranian Journal of Public Health vol 39no 2 pp 69ndash76 2010

[53] R Galanello and R Origa ldquo120573-thalassemiardquoOrphanet Journal ofRare Diseases vol 5 no 1 article 11 2010

[54] S L Thein ldquoGenetic modifiers of 120573-thalassemiardquo Haematolog-ica vol 90 no 5 pp 649ndash660 2005

[55] D J Weatherall ldquoSingle gene disorders or complex traitslessons from the thalassaemias and other monogenic diseasesrdquo

The British Medical Journal vol 321 no 7269 pp 1117ndash11202000

[56] Z Rahimi A Muniz R Akramipour et al ldquoHaplotype anal-ysis of 120573 thalassemia patients in Western Iranrdquo Blood CellsMolecules and Diseases vol 42 no 2 pp 140ndash143 2009

[57] M Yavarian M Karimi E Bakker C L Harteveld and PC Giordano ldquoResponse to hydroxyurea treatment in Iraniantransfusion-dependent 120573-thalassemia patientsrdquoHaematologicavol 89 no 10 pp 1172ndash1178 2004

[58] H Nemati Z Rahimi and G Bahrami ldquoThe Xmn1 polymor-phic site 51015840 to the 119866120574 gene and its correlation to the 119866120574 119860120574ratio age at first blood transfusion and clinical features in120573-thalassemia patients from Western Iranrdquo Molecular BiologyReports vol 37 no 1 pp 159ndash164 2010

[59] M T Akbari P Izadi M Izadyar K Kyriacou and M Klean-thous ldquoMolecular basis of thalassemia intermedia in IranrdquoHemoglobin vol 32 no 5 pp 462ndash470 2008

[60] M Hamid F Mahjoubi M T Akbari A Arab S Zeinali andM Karimipoor ldquoMolecular analysis of 120574-globin promoters HS-111 and 31015840HS1 in 120573-thalassemia intermedia patients associatedwith high levels of Hb Frdquo Hemoglobin vol 33 no 6 pp 428ndash438 2009

[61] D R Higgs andD JWeatherall ldquoThe 120572 thalassaemiasrdquoCellularand Molecular Life Sciences vol 66 no 7 pp 1154ndash1162 2009

[62] C L Harteveld M Yavarian A Zorai E D Quakkelaar Pvan Delft and P C Giordano ldquoMolecular spectrum of 120572-thalassemia in the Iranian population of hormozgan threenovel point mutation defectsrdquo The American Journal of Hema-tology vol 74 no 2 pp 99ndash103 2003

[63] K Zandian J Nateghi B Keikhaie et al ldquo120572-thalassemiamutations inKhuzestan Province Southwest IranrdquoHemoglobinvol 32 no 6 pp 546ndash552 2008

[64] F Hossein R Mohsen M Mohsen and M Taheri ldquo120572-thala-ssemia mutations in two provinces of Southern Iran Fars ampKohkeloye and Bouyer Ahmadrdquo Hemoglobin vol 36 no 2 pp139ndash143 2012

[65] A Tamaddoni V Hadavi N H Nejad et al ldquo120572-thalassemiamutation analyses in mazandaran province north iranrdquoHemo-globin vol 33 no 2 pp 115ndash123 2009

[66] V Hadavi M Jafroodi N Hafezi-Nejad et al ldquo120572-thalassemiamutations in Gilan Province North Iranrdquo Hemoglobin vol 33no 3-4 pp 235ndash241 2009

[67] N Saleh-Gohari and A Khosravi-Mashizi ldquoSpectrum of 120572-globin gene mutations in the Kerman province of IranrdquoHemoglobin vol 34 no 5 pp 451ndash460 2010

[68] VHadavi AHTaromchiMMalekpour et al ldquoElucidating thespectrum of 120572-thalassemia mutations in Iranrdquo Haematologicavol 92 no 7 pp 992ndash993 2007

[69] S T Singer ldquoVariable clinical phenotypes of 120572-thalassemia syn-dromesrdquoTheScientificWorldJournal vol 9 pp 615ndash625 2009

[70] S Zeinali M Fallah and H Bagherian ldquoHeterogeneity ofhemoglobin H disease in childhoodrdquoThe New England Journalof Medicine vol 364 no 21 pp 2070ndash2071 2011

[71] A R Cohen R Galanello D J Pennell M J Cunninghamand E Vichinsky ldquoThalassemiardquo HematologyAmerican Societyof Hematology Education Program pp 14ndash34 2004

[72] M Yavarian M Karimi A Zorai C L Harteveld and P CGiordano ldquoMolecular basis of Hb H disease in southwest IranrdquoHemoglobin vol 29 no 1 pp 43ndash50 2005

[73] S Ebrahimkhani A Azarkeivan N Bayat et al ldquoGenotype-phenotype correlation in Iranian patients with Hb H diseaserdquoHemoglobin vol 35 no 1 pp 40ndash46 2011


[74] A Samavat and B Modell ldquoIranian national thalassaemiascreening programmerdquoTheBritishMedical Journal vol 329 no7475 pp 1134ndash1137 2004

[75] M Ghanei P Adibi M Movahedi et al ldquoPre-marriage pre-vention of thalassaemia report of a 100000 case experience inIsfahanrdquo Public Health vol 111 no 3 pp 153ndash156 1997

[76] A Christianson A Streetly and A Darr ldquoLessons from thalas-saemia screening in IranrdquoThe British Medical Journal vol 329no 7475 pp 1115ndash1117 2004

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


polymorphism in human populations [4] Epidemiologicin vitro and in vivo studies support association betweenstructural variants of Hb S Hb C and Hb E as well as 120572-and 120573-thalassemia with areas of prevalence of Plasmodiumfalciparum [5]

The Hb S variant decreases the risk of infection by P fal-ciparum The mechanism of red blood cells (RBC) resistancein sickle cell trait (AS) individuals could be due to the lack ofparasite development and accelerating Hb S polymerizationin lowO

2tension andhigher rates of phagocytosis of parasite-

infected sickle erythrocyte by host immune cells [4 5] TheHb AS protects against all forms of malaria by elimination ofparasites in 90 of Hb S cell populations In Hb S carriers theselection occurs at the cost of the loss of homozygotes fromsickle cell disease [4 6]

The selective advantage of Hb C is greater in homozygousstate (90) than in Hb AC carriers (30) [6]

The protection of 120573-thalassemia patients against malariais due to delay of switching from fetal to adult hemoglobinresulting in higher level of intracellular Hb F The Hb F ismore stable and stronger than Hb A and is partially resistantto digestion by proteolytic machine of parasite So Hb Fcontaining red cells are inadequate hosts for P falciparumand this hemoglobin protects the host from the lethality ofmalaria [5] Also the presence of higher levels of serumantibodies bound to 120573-thalassemic erythrocytes is the othermechanism provides the protection against malaria in thesepatients [4]120572-Thalassemia is very prevalent in malaria endemic regi-

ons which protects against severe forms of P falciparuminfectionThe infected erythrocytes of 120572-thalassemia patientshave high levels of antibodies on their surface that promoteantiparasite effects [4] The protection of 120572+-thalassemiaagainst malaria might be due to higher susceptibility of hom-ozygotes tomalaria in early life that immunize these individu-als and make them resistance to malaria later [7] The prote-ctive effect of 120572-thalassemia is specific to severe malaria [6]

Iran as an eastern Mediterranean country with mediummalaria endemicity [8] started the program of malaria eradi-cation in 1956 Later in 1980 the program changed to malariacontrol program Now this disease is mostly restricted tothree southeastern provinces of Sistan-BaluchestanHormoz-gan and Kerman [9] According toWHOmalaria report Iranis classified in the preelimination stage ofmalaria [10] Due toheterozygote advantage against P falciparum malaria thereis a high incidence of the 120573-thalassemia in Iran especiallyin northern and southern Iran as the ten provinces withhigh prevalence of 120573-thalassaemia are Gilan HormozganKhuzestan Kohgiluyeh-Boyer-Ahmad Fars Bushehr Sistan-Baluchestan Kerman and Isfahan in northern and southernIran [11 12] The Sistan-Balouchestan province that is themost prevalent area for malaria comprises 42ndash60 of totalmalaria cases of Iran Majority of infected cases (85) withmalaria were due to P falciparum [13] Isfahan provincelocated in central Iran has been classified as the sixth moreprevalent province for malaria after Sistan-BalouchestanHormozgan Kerman Fars and Tehran provinces [14]

The gene frequency of 120573-thalassaemia has been estimatedto be 00174 with over 225 million carriers [15] An overall

rate of consanguineous marriage (majority first-cousin mar-riages) is 386 (ranges from 16 to 47) in Iran [15]

3 Structural Variants

31 Hemoglobin S The hemoglobin (Hb) S that results fromglutamic acidrarr valine amino acid substitution at position6 of 120573-chain is the most clinically important structuralvariant of hemoglobin with highest frequency in AfricaSaudi Arabia and India Sickle cell disease (SCD) resultsfrom the homozygous state of the mutation or a compoundheterozygous state with one of structural variants of Hb D-Punjab Hb O-Arab Hb C or 120573-thalassemia mutation in theother 120573-genes [16 17]

First report of clinical and hematological features of sicklecell anemia in southern Iran demonstrated the high level ofHb F (18) and mild clinical course of the disease in Iranianpatients [18] The prevalence of sickle cell trait and sickle cellanemia in southern Iran has been estimated to be around 143and 01 respectively [19] In central Iran (southeast Isfahan)sickle cell trait was reported with a frequency of 833 [20]In contrast in western Iran the lowest frequency for thishemoglobin variant compared to structural variants of HbD-Punjab Hb Q-Iran and Hb Setif was reported [21]

32 Hb D-Punjab Hb D-Punjab (D-Los Angeles) is char-acterized by substitution of glutamine for glutamic acid atposition of 121 of 120573-globin chain [22] The presence of HbD-Punjab in combination with an 120572-chain variant (Hb O-Indonesia) in an Iranian patient was reported 37 years agoby Rahbar et al [23] The case had no hemolytic disordersand clinical symptoms Subsequent report indicated that inKurdish population from western Iran Hb D-Punjab was themost prevalent structural 120573-globin variant [22]

Hb D-Punjab was detected as the second prevalentstructural variant in southern province of Khuzestan [24]Mild clinical presentation of this variant in homozygous andcombined heterozygous state with a 1205730-thalassemic mutationand also with concomitant presence of 120572- and 1205730-thalassemiamutations have been indicated [22] Benign feature of Hb D-Punjab was confirmed by two separate reports of concomi-tant presence of this structural variant with 120573-thalassemiamutation of IVSII-1GA that produced aminor120573-thalassemiapicture [25 26]

33 HbQ-Iran Single nucleotidemutations in 1205721 or 1205722 genesproduce abnormal 120572-chain hemoglobins Hb Q disordersincluding Hb Q-Iran [12057275 (EF4) AsprarrHis] Hb Q-Thailand[12057274 (EF3) AsprarrHis] and Hb Q-India [12057264 (E13) AsprarrHis] are important Hb variants All of these hemoglobinsare slow moving variants that migrate at the electrophoreticposition of Hb S at alkaline pH [27 28] In carriers of Hb Q-Iran this hemoglobin has a level of 17ndash19 and hematologicalindices are normal [29] In recent studies from Kurdishpopulation of western Iran this Hb variant was the secondprevalent structural variant with a level of 142ndash293 andin carriers of this hemoglobin hematological indices werenormal [21 29]








4 Thalassemia











































Western Iran










2and Hb


6 Conclusion



Caspian Sea

Persian Gulf

Oman Sea

GolestanMazandaran

Gilan

TehranHamadan

Kermanshah

Kurdistan

Lorestan

Fars

Hormozgan

Bushehr

Kerman

Ardabil

Ilam

Khuzestan

Isfahan

Khorasan

West Azerbaijan

Sistan-Baluchestan

East Azerbaijan




Genetic Terms













References























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























4 Thalassemia











































Western Iran










2and Hb


6 Conclusion



Caspian Sea

Persian Gulf

Oman Sea

GolestanMazandaran

Gilan

TehranHamadan

Kermanshah

Kurdistan

Lorestan

Fars

Hormozgan

Bushehr

Kerman

Ardabil

Ilam

Khuzestan

Isfahan

Khorasan

West Azerbaijan

Sistan-Baluchestan

East Azerbaijan




Genetic Terms













References























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































Western Iran










2and Hb


6 Conclusion



Caspian Sea

Persian Gulf

Oman Sea

GolestanMazandaran

Gilan

TehranHamadan

Kermanshah

Kurdistan

Lorestan

Fars

Hormozgan

Bushehr

Kerman

Ardabil

Ilam

Khuzestan

Isfahan

Khorasan

West Azerbaijan

Sistan-Baluchestan

East Azerbaijan




Genetic Terms













References























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Caspian Sea

Persian Gulf

Oman Sea

GolestanMazandaran

Gilan

TehranHamadan

Kermanshah

Kurdistan

Lorestan

Fars

Hormozgan

Bushehr

Kerman

Ardabil

Ilam

Khuzestan

Isfahan

Khorasan

West Azerbaijan

Sistan-Baluchestan

East Azerbaijan




Genetic Terms













References























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Genetic Epidemiology, Hematological and Clinical Features...

Documents

Transcript of Review Article Genetic Epidemiology, Hematological and Clinical Features...