Review Article Clinical Relevance of HLA Gene Variants in ...downloads.hindawi.com/journals/jir/2016/9069375.pdf · gen (HLA) classes I and II alleles as well as non-HLA genes, in

Review ArticleClinical Relevance of HLA Gene Variants in HBV Infection

Li Wang1 Zhi-Qiang Zou1 and Kai Wang2

1 Infectious Disease Hospital of Yantai 62 Huanshan Road Zhifu District Yantai Shandong 264001 China2HepatologyDepartment QiluHospital of ShandongUniversity 44WenhuaWest Road LixiaDistrict Jinan Shandong 250012 China

Correspondence should be addressed to Li Wang liliwang2200163com

Received 22 February 2016 Accepted 14 April 2016

Academic Editor Oscar Bottasso

Copyright copy 2016 Li Wang et alThis 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

Host gene variants may influence the natural history of hepatitis B virus (HBV) infection The human leukocyte antigen(HLA) system the major histocompatibility complex (MHC) in humans is one of the most important host factors that arecorrelated with the clinical course of HBV infection Genome-wide association studies (GWASs) have shown that single nucleotidepolymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but alsospontaneous HBV clearance and seroconversion disease progression and the development of liver cirrhosis and HBV-relatedhepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) These variations also influence the efficacy of interferon (IFN)and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines Meanwhile discrepant conclusions were reached withdifferent patient cohorts It is therefore essential to identify the associations of specific HLA allele variants with disease progressionand viral clearance in chronic HBV infection among different ethnic populations A better understanding of HLA polymorphismrelevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBVin different areas and ethnic groups to improve strategies for the prevention and treatment of chronic HBV infection

1 Introduction

Certain host gene variants including human leukocyte anti-gen (HLA) classes I and II alleles as well as non-HLA genesinfluence the natural history of hepatitis B virus (HBV)infection The HLA system the major histocompatibilitycomplex (MHC) in humans is one of themost important hostfactors correlated with the clinical course of HBV infectionThe highly polymorphic HLA classes I and II genes can affectthe ability of HLA molecules to trigger immune responseswhich affects the outcome of infection by any given pathogen[1] HBV peptides presented by HLA class I molecules tocytotoxic T lymphocytes (CTLs) are critical in the eradicationof HBV infection by boosting CTL ability to identify and killHBV-infected cells [2 3]

The discordance between HBV-specific CD8+ T cell rep-ertoires present in different ethnic groups such as Caucasianand Chinese subjects was shown to reflect the ability ofHLA micropolymorphisms to diversify T cell responses [4]Previous studies have revealed the associations of certainHLA class I genes with the course of HBV infection [5]

HLA class II molecules are cell surface glycoproteins ofantigen presenting cells (APCs) which are responsible forpresenting exogenous antigens to CD4+ T-helper cells Anti-gen presentation efficiency may vary due to gene loci [6]Genome-wide association studies (GWASs) have shown thatsingle nucleotide polymorphisms (SNPs) near HLA-DPHLA-DQ and HLA-DR loci are significantly correlated withHBV infection outcomes [7ndash9] HLA class II gene variationsare strongly associated with not only persistent HBV infec-tion but also spontaneousHBV clearance and seroconversion[10 11] disease progression and the development of livercirrhosis (LC) and HBV-related hepatocellular carcinoma(HCC) in chronic hepatitis B (CHB) [7 12 13] Such varia-tions also affect interferon (IFN) and nucleot(s)ide analogue(NA) treatment efficacy and the response to HBV vaccinesMeanwhile discrepant conclusions are reached in differentcohorts [14] For instance the candidate variant rs9277535(550AG) in the 31015840 untranslated region (31015840UTR) of the HLA-DPB1 gene associated most significantly with CHB andHBVinfection outcomes in Asians was shown to have a minimaleffect on HBV recovery in European American and African

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2016 Article ID 9069375 7 pageshttpdxdoiorg10115520169069375

2 Journal of Immunology Research

American subjects [15] It is therefore critical to identifythe associations of specific HLA allele variants with diseaseprogression and viral clearance in chronic HBV infectionsamong different ethnic groups

A deeper understanding of HLA polymorphism rele-vance in HBV infection outcome would help elucidate therole of HLA SNPs in the pathogenesis and clearance of HBVin different areas and ethnicities to improve strategies forthe prevention and treatment of chronic HBV infectionThisreview summarizes the reported associations of HLA poly-morphisms with susceptibility to HBV infection resolutiondisease progression and antivirus treatment efficacy andresponse to HBV vaccines

2 Associations of HLA Gene Variantswith Susceptibility and Persistence ofHBV Infection

Though several GWASs have revealed the association of genevariants in the HLA region with chronic HBV infectionthe susceptibility gene loci and potential mechanisms havenot been fully identified A comparative review showed thatHLA-DRB1lowast11lowast12 alleles andDQB1lowast0301 are associated withHBV persistence globally [14] A Chinese study by Zhu et al[16] identified four loci that independently drive chronicHBV infection including HLA-DP1205731 positions 84ndash87 HLA-DR1205731lowast13 sites 71 and rs400488 and HLA-C position 15In another study [17] after genotyping 140 SNPs withinthe HLA-DPDQ genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls 76 SNPsand 5 LD blocks were identified in HLA-DPDQ clustersindependent of each other which are significantly associatedwith HBV infection rs9277535 in HLA-DPB1 was found tobe the most significant locus Chang et al [18] found thatrs9277535 (HLA-DPB1) rs9276370 (HLA-DQA2) rs7756516and rs7453920 (HLA-DQB2) and rs9366816 nearHLA-DPA3are significantly associated with persistent HBV infectionespecially the ldquoT-Trdquo haplotype composed of rs7756516 andrs9276370 that is more prevalent in severe disease subgroupsand associated with nonsustained therapeutic response (119875 =00262) inmale TaiwanHanChinese individuals DQB1lowast0301and DQB1lowast0303 are correlated with continuous infection inXinjiang Uygur Chinese subjects [8]

A transethnic association analysis [19] performed amongAsian populations including Japanese Korean Hong Kongand Thai subjects revealed Asian-specific associations ofHLA-DPA1 and HLA-DPB1 alleleshaplotypes with HBVinfection and disease progression The latter study identifieda new risk allele HLA-DPB1lowast0901 and a new protective alleleDPB1lowast0201 in chronic HBV infection An American study[15] showed that the HLA-DPB1 31015840UTR 496GG genotypeconfers latent susceptibility to persistent HBV infection andis also associated with significantly higher levels of HLA-DP surface protein expression in healthy donors suggestingthat differences in HLA-DP expression may increase the riskfor persistent HBV infection in European Americans andAfrican Americans A prospective study [20] showed thatclass II alleles DQA1lowast0501 (119875 = 005) and DQB1lowast0301

(119875 = 001) the two-locus haplotype consisting of the lattertwo alleles and the three-locus haplotype DQA1lowast0501DQB1lowast0301 and DRB1lowast1102 (OR = 107 119875 = 001) aresignificantly associated with persistent HBV infection in anAfrican American cohort

In addition HBV persistence was shown to be associatedwith class II allelic homozygosity Interestingly three SNPsbelonging to the HLA-DQ region (rs2856718 rs7453920and rs9275572) shown to display increased susceptibilityto chronic HBV infection were detected in Saudi Arabianpatients [21] Meanwhile DRB1lowast08 and DRB1lowast09 alleleswhich are susceptible to HBV infection were found inBrazilian populations determined in young and male blooddonors [9] A study [22] identified 2 risk alleles in MHC locinamely HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535)using salivary DNA extracted with a modified protocol fromblood samples in Chinese patients This provides a newnoninvasive screening method for identifying risk loci

Furthermore HLA gene variants are also associatedwith susceptibility to vertical transmission Multiple factorsincluding HBV structure and DNA level placental barrierthe immune status of the mother and the genetic back-ground of the newborn infant determine the susceptibilityto intrauterine HBV infection Xu et al [23] assessed 15HLA-DR alleles and found HLA-DRB1lowast07 to be the onlyone associated with infant susceptibility to intrauterine HBVinfection

On the other hand gene polymorphisms of some HLAloci confer protective effects against persistentHBV infectionIt was shown that the HLA-DPA1 and HLA-DPB1 genesare significantly associated with protective effects againstCHB in Japanese Korean and other Asian populationsincluding Chinese and Thai individuals [19] Cross-sectionalstudies showed that HLA-DRB1lowast1301-02 are associated withprotection against persistent HBV infection in GambiaGermany and Korea [24ndash26] China has the highest HBVprevalence rate in the world with different ethnic popula-tionsWang et al [27] demonstrated that in two independentcase-control studies HLA-DP A alleles of both rs3077 andrs9277535 significantly decrease the risk for CHB in ChineseHan subjects while HLA-DP rs9277535 is associated withdecreased risk in Chinese Zhuang subjects In additionHLA-DQB1lowast0201 is HBV resistance gene in Xinjiang Uygurethnic groups of China [8] Although the most significantassociations were observed for HLA-DPA1 rs3077 and HLA-DPB1 rs9277535 A alleles (decreased risk for HBV infectionin Asian populations) only a highly significant associationof HLA-DPA1 rs3077 with HBV infection was observed inCaucasians [28]

3 Associations of HLA Gene Variantswith Spontaneous HBsAg Clearanceand HBV Eradication

Spontaneous HBsAg seroclearance occurs in a very smallproportion of patients with chronic HBV infection Themechanisms of spontaneous HBV clearance are determinedby the interactions between HBV and the host immuneresponse including innate and adaptive immune responses

Journal of Immunology Research 3

which are affected by specific HLA gene polymorphismsthat alter peptide epitope binding For instance HLA-DPA1and HLA-DPB1 which encode the HLA-DP 120572 and 120573 chainsmay be involved in antigen presentation to CD4+ positive Tlymphocytes which is important for HBV clearance [27 29]HLA-DR13 is consistently associated with HBV clearanceglobally [14 24 30 31] A meta-analysis indicated that sub-jects harboring at least one A allele of HLA-DPB1 rs9277535and HLA-DPA1 rs3077 variants have increased susceptibilityto spontaneous HBV clearance compared with those withG alleles [7] Three SNPs of the HLA-DP gene includingrs9277535 rs7453920 and rs2856718 confer increased fre-quency of HBsAg clearance in China [10] Hu et al [12]showed a significantly higher proportion of the rs9277534minor allele A in spontaneous HBV clearance than in theHBV persistent infection group (119875 lt 00001) Genotypicanalyses [5] showed that GA and AA genotypes are asso-ciated with spontaneous HBV clearance In addition HLA-Blowast130101G frequency is associated with spontaneousHBsAgclearance in a QidongHanChinese population HBV carrierswith rs9277535 non-GG genotype and GA haplotype have ahigher chance to clear HBsAg in Chinese subjects of Taiwan[32] The rs3077 and rs9277542 alleles in the HLA-DPA1in HLA-DPB1 genes respectively confer protective effectson HBV infection and clearance in Japanese and Koreanpopulations [19] In a study assessing European and AfricanAmerican populations rs9277534 rather than rs9277535 inthe HLA-DPB1 31015840UTR was shown to be associated withHBV recovery [33] A meta-analysis of 62050 subjects from29 case-control studies showed that rs3077 and rs9277535in HLA-DP significantly decrease HBV infection risks andincrease HBV clearance [34] The 496AG variant has astronger effect than any individual HLA-DPB1 or DPA1 alleleas well as other HLA alleles associated with HBV recoveryin European American cohort [15] Li et al [35] showed thatHLA-Blowast15 and DRB1lowast11 and DRB1lowast14 are associated withspontaneous recovery in patients with HBV subgenotype C2infection in Northeast China

HLA-DR2 HLA-DRlowast0406 HLA-Blowast4001 and HLA-DR7antigens are associated with protective effect on acute HBVinfection [19 36 37] It is known that patients who success-fully resolve acute hepatitis B infection develop strong HLAclasses I and II restricted T cell response which is weakor absent in patients with chronic hepatitis B [38 39] InSpain Cotrina et al [40] found that the HLA-DRB1lowast1301 andDRB1lowast1302 alleles are associated with infection resolutionin acute hepatitis B Li et al [35] also showed that HLA-Blowast07 andDRB1lowast13 may protect subjects fromHBV infectionHLA-DQ rs2856718G and rs9275572A are strongly associatedwith decreased risk of chronic HBV infection and naturalclearance [41]

4 Associations of HLA GeneVariants with Early Hepatitis B e Antigen(HBeAg) Seroconversion

HBeAg seroconversion mainly depends on patient age atinfection and the host immune responses It was shown

that the functional stage of dendritic cells (DCs) plays animportant role in HBeAg seroconversion [42] DCs are themost effective antigen presenting cells and play a pivotalrole in antiviral response induction Exogenous antigens arephagocytized and then loaded on both HLA classes I and IIby DCs Therefore HLA gene variants may influence hostinduced early HBeAg seroconversion A long-term cohortstudy demonstrated that HLA class I antigen B61 and classII antigen DQB1lowast0503 are associated with early HBeAgseroconversion in CHB children in Taiwan [43] Althoughthe HLA-DPA1 SNP did not show a statistically significantassociation with early HBeAg seroconversion in Japanesechildren it tended to increase the likelihood of achievingearly spontaneous HBeAg seroconversion [44] In an AfricanHIV-positive cohort it was suggested that HLA-A allelesalone other than HLA-B or HLA-C indeed predict HBeAgstatus (AUC = 073 119875 = 0002) [45] These results emphasizethe role of the CD8+ T cell response in HBV control

5 Association of HLA Gene Variants withthe Risk for Developing Liver Cirrhosis andHBV-Related Hepatocellular Carcinoma

HLA gene variations are strongly associated with not onlyHBV infection persistence or clearance but also diseaseprogression and the development of liver cirrhosis (LC)andHBV-related hepatocellular carcinoma (HCC) HLA-DQpolymorphism analysis [41] using matrix-assisted laser des-orptionionization time of flight mass spectrometry showedthat rs9275572A is associatedwith the development of cirrho-sis and HCC (OR = 0632 P = 0008) Of the SNPs reportedin HBV-related HCC GWASs rs9267673 near C2 rs2647073and rs3997872 near HLA-DRB1 and rs9275319 near HLA-DQwere found to be significantly associated with the risk forHBV-related LC [46] suggesting that gene variants associatedwith HBV-related hepatocarcinogenesis may already playan important role in the progression from CHB to LCTherefore understanding HLA genetic background wouldhelp improve current HCC surveillance programs in HBV-infected patients

GWAS on genetic susceptibility of HBV-related HCCindicated two consistently identified tagging SNPs aroundHLA-DQDR [47 48] A multicenter case-control studyincluding 1507HBV-related HCC cases and 1560HBV per-sistent carriers as controls showed that HBV carriers infectedwith HBV genotype C and carrying HLA-DQDR SNPs(rs9272105AAgenotype rs9275319AAgenotype) have a rela-tively high risk for HCC [49] Other studies [10 13] suggestedthat HLA-DP rs3077 and rs9277535 polymorphisms areassociated withHCC susceptibility in Asian individuals FourSNPs (rs17875380 rs41557518 rs114465251 and rs115492845)in nonclassical class I alleles were shown to be associatedwith altered susceptibility to HBV or HCC while HLA-Flowast0104 HLA-Glowast0105N and HLA-Elowast0101 are associatedwith hepatitis B or hepatitis B complicated with HCC Six of16 designated HLA-E HLA-G and HLA-F haplotypes wereshown to be associated with risk for hepatitis B or HCC [50]


On the other hand HLA gene variations also decreasethe risk for cirrhosis and HCC Doganay et al [51] foundin a multivariate logistic regression analysis that DRB1lowast07is a significant negative predictor of cirrhosis (119875 = 0015)This may be due to the fact that a polymorphic aminoacid sequence in DRB1lowast07 alters interaction with the T cellrecognition site Mohamadkhani et al [29] revealed that thers2856718 variant significantly diminishes the host risk forHCC Zhang et al [13] also indicated that the HLA-DP SNPrs3077 might act beneficially against HCC susceptibility Inanother studyHLA-DP rs3077 rs9277535 and rs7453920 alsoshowed no association with HCC development [52]

Killer cell immunoglobulin-like receptors (KIRs) areinvolved in the regulation of NK cell activation throughrecognition of specific HLA class I allotypes In amultivariateCox model Pan et al [53 54] suggested that KIR and HLAgenetic background can influence the age at HCC onsetin male patients and is associated with HCC incidence inpatients with HBV infection

6 HLA Gene Variants Associated with Efficacyof Interferon- (IFN-) 120572 and NAs Treatment

Interferon- (IFN-) 120572 is the first-line therapy for CHB patientsbut initiates a complete response only in a minority ofpatients HLA gene variants have also been shown to beassociatedwith response to IFN-120572 treatment inCHBpatientsDifferent haplotypes of the same SNPmay be associated withdifferent clinical treatment outcomes It was shown that theldquoG-Crdquo haplotype of the five SNPs including rs9277535 (HLA-DPB1) rs9276370 (HLA-DQA2) rs7756516 and rs7453920(HLA-DQB2) and rs9366816 near HLA-DPA3 is associatedwith sustained therapeutic response to IFN-120572 treatment inmale Han Taiwanese subjects (119875 = 00132 OR = 249)[18] In a large cohort of Caucasian chronic hepatitis Bpatients infected with the HBV genotype A or D Brouwer etal demonstrated that HLA-DPB1 polymorphisms are inde-pendently associated with both virological and serologicalresponses to PEG-IFN therapy at 6 months after treatment

HLA-DPA1 and HLA-DPB1 haplotype block GG showedcomparable results for virological and combined response[55] Han et al [56] suggested that HLA-DRB1lowast14 allele maybe associated with a high rate of the response of CHB patientsto IFN treatment Compared with other HLA-DQB1 allelesHLA-DQB1lowast07 may be associated with low response rate toIFN

Cheng et al [57] showed by multivariate analysis that at6 months of PEG-IFN-120572 therapy and 6 months after ther-apy rs3077-GG genotype is independently associated withhigher HBeAg loss and anti-HBeAb seroconversion ratesmeanwhile the rs9277535-GG genotype was independentlyassociatedwith declinedHBVDNA levels inChinese patientswith CHB Similar results were observed in Taiwan [58]

The HLA-DQ locus rs9275572 is a predictor of viral andbiochemical responses to lamivudine (LAM) therapy in HanChinese subjects [41] Hosaka et al [59] demonstrated anassociation of HLA-DP polymorphisms with ge2 A allelesat rs3077 and rs9277535 and decreased HBsAg levels andseroclearance amongHBeAg-positive Japanese CHB patients

treated with LAM Meanwhile the HLA-DRB1lowast010101 alleleis closely associated with poor virological response to initialLAM therapy in Korean CHB patients [60] Chang et al[18] also showed that in patients with the TT genotypeof rs9276370 (HLA-DQA2) there is a higher nonsustainedresponse rate especially in the LAM (119875 = 00074) and PEG-IFN-120572-2a (119875 = 00814) groups rather than in entecavirtreated individuals A randomized clinical trial [61] assessingPEG-IFN-120572-2b with or without entecavir in patients withHBeAg-negative CHB revealed the GG genotype of rs3077(HLA-DPA1) as an independent predictor of therapeuticresponse

7 HLA Gene Variants Associated withResponse to Hepatitis B Vaccination

Accumulating evidence shows that certain HLA types areassociated with decreased or increased antibody responseto hepatitis B vaccines in different individuals A meta-analysis [62] including 774 potentially relevant articles anda total of 2308 subjects (1215 responders 873 nonrespondersand 220 control populations) and assessing the effect ofHLA on immunological response to hepatitis B vaccinesin healthy individuals showed that for DRB1 alleles thethree HLA variants DRB1lowast01 DRB1lowast1301 and DRB1lowast15 areassociated with significantly increased antibody response tohepatitis B vaccines with pooled ORs of 273 594 and 229respectively Meanwhile DRB1lowast03 (DRB1lowast0301) DRB1lowast04DRB1lowast07 andDRB1lowast1302 showed opposite results For DQB1alleles DQB1lowast05 (DQB1lowast0501) DQB1lowast06 and DQB1lowast0602were shown to be associated with markedly increased anti-body response to hepatitis B vaccine with pooled ORs of185 235 234 and 332 respectively DQB1lowast02 (pooled OR= 027) showed opposite results Mert et al [63] found pos-itive correlations between four HLA-DR (HLA-DRB1lowast04XDRB1lowast0401X DRB1lowast1113 andDRB1lowast0401X0201) haplotypesand nonresponders but a negative correlation with one classI (HLA-B13) in Turkey In Korean infants [64] who receivedHBV vaccination HLA-Alowast33 B62 DRB1lowast04 and DRB1lowast07alleles showed positive associations with nonresponsiveness(lt10mIUmL) or low antibody titers (lt100mIUmL) whilealleles Alowast02 and DRB1lowast08 showed negative associationsAfter stratification by other associated alleles at differentloci B62 and DRB1lowast07 were still independently associatedwith nonresponsiveness So upon evaluating the responseto HBV vaccination different HLA types of ethnic groupsshould be taken into consideration HLA gene frequencies ofdistinct ethnic groups should be examined in further large-scale population-based studies [65]

8 Summary and Perspectives

Overall the complicated nature history of HBV infectionmakes it necessary to find clinical and genetic markers tohelp predict individuals at higher risk to develop CHB andworse outcomes such as LC and HCC The HLA systemis an integral component of the host immune responseThe highly polymorphic HLA genes are key factors in theactivation of the immune response against HBV infection


through their enormous capacity of attracting and bindingviral peptides HLA gene variations are associated not onlywith susceptibility or resistance to HBV infection but alsowith spontaneous HBV clearance disease progression effi-cacy of antiviral treatment and response to HBV vaccinesFurthermore specific HLA allele variants may have differentimpact on clinical outcomes of chronic HBV infectionsamong different ethnic subjects Identifying the associationsof specific HLA allele variants with disease progression orviral clearance in chronic HBV infections among differentethnic populations needs further assessment in larger scalecontrolled clinical trials

Finally upon evaluating the impact of HLA gene variantson HBV infection SNP-SNP interactions between HLA andother host genes such as granulysin (GNLY) SNPs [66] andpolymorphisms in toll-like receptor-interferon (TLR-IFN)[67] pathway genes and HBV mutations [68] should also bekept in mind

Competing Interests

The authors declare that they have no competing interests

Authorsrsquo Contributions

LiWang and Zhi-Qiang Zou contributed equally to the work

References

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[2] X Chen W Wang S Wang et al ldquoAn immunodominantHLA-Alowast1101-restrictedCD8+T-cell response targeting hepatitisB surface antigen in chronic hepatitis B patientsrdquo Journal ofGeneral Virology vol 94 part 12 pp 2717ndash2723 2013

[3] Q Liu Y Zheng Y Yu Q Tan and X Huang ldquoIdentification ofHLA-Alowast0201-restricted CD8+ T-cell epitope C

64minus72from hep-

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[4] A T Tan E Loggi C Boni et al ldquoHost ethnicity and virusgenotype shape the hepatitis B virus-specific T-cell repertoirerdquoJournal of Virology vol 82 no 22 pp 10986ndash10997 2008

[5] F Miao H Sun N Pan et al ldquoAssociation of human leukocyteantigen class i polymorphism with spontaneous clearance ofhepatitis b surface antigen in qidong han populationrdquo Clinicaland Developmental Immunology vol 2013 Article ID 145725 7pages 2013

[6] X Guo Y Zhang J Li et al ldquoStrong influence of humanleukocyte antigen (HLA)-DP gene variants on development ofpersistent chronic hepatitis B virus carriers in the Han Chinesepopulationrdquo Hepatology vol 53 no 2 pp 422ndash428 2011

[7] K Matsuura M Isogawa and Y Tanaka ldquoHost genetic variantsinfluencing the clinical course of Hepatitis B virus infectionrdquoJournal of Medical Virology vol 88 no 3 pp 371ndash379 2016

[8] Y Zhang F Zhao L Lan Z Qin and L Jun ldquoCorrelationof HLA-DQB1 gene polymorphism of Xinjiang Uygur withoutcome ofHBV infectionrdquo International Journal of Clinical andExperimental Medicine vol 8 no 4 pp 6067ndash6072 2015

[9] B D M Correa E P D A Lopes M D F P M de Albu-querque and L Dourado ldquoAssociation between HLA-DRB1lowastpolymorphisms and hepatitis B infection in a Brazilian popu-lationrdquo Revista da Associacao Medica Brasileira vol 58 no 5pp 537ndash542 2012

[10] LHu X Zhai J Liu et al ldquoGenetic variants in human leukocyteantigenDP-DQ influence both hepatitis B virus clearance andhepatocellular carcinoma developmentrdquoHepatology vol 55 no5 pp 1426ndash1431 2012

[11] W-K Seto D K-HWongM Kopaniszen et al ldquoHLA-DP andIL28B polymorphisms influence of host genome on hepatitisB surface antigen seroclearance in chronic hepatitis Brdquo ClinicalInfectious Diseases vol 56 no 12 pp 1695ndash1703 2013

[12] Z Hu J Yang G Xiong et al ldquoHLA-DPB1 variant effect onhepatitis B virus clearance and liver cirrhosis developmentamong Southwest Chinese populationrdquo Hepatitis Monthly vol14 no 8 Article ID e19747 2014

[13] X Zhang C Zheng Z H Zhou et al ldquoRelationship betweenHLA-DP gene polymorphisms and the risk of hepatocellularcarcinoma a meta-analysisrdquo Genetics and Molecular Researchvol 14 no 4 pp 15553ndash15563 2015

[14] R Singh R Kaul A Kaul and K Khan ldquoA comparative reviewof HLA associations with hepatitis B and C viral infectionsacross global populationsrdquo World Journal of Gastroenterologyvol 13 no 12 pp 1770ndash1787 2007

[15] R Thomas C L Thio R Apps et al ldquoA novel variant markingHLA-DP expression levels predicts recovery from hepatitis Bvirus infectionrdquo Journal of Virology vol 86 no 12 pp 6979ndash6985 2012

[16] M Zhu J Dai C Wang et al ldquoFine mapping the MHC regionidentified four independent variants modifying susceptibilityto Chronic Hepatitis B in Han Chineserdquo Human MolecularGenetics vol 25 no 6 pp 1225ndash1232 2016

[17] J Tao K Su C Yu et al ldquoFinemapping analysis ofHLA-DPDQgene clusters on chromosome 6 reveals multiple susceptibilityloci for HBV infectionrdquo Amino Acids vol 47 no 12 pp 2623ndash2634 2015

[18] S-W Chang C S-J Fann W-H Su et al ldquoA genome-wideassociation study on chronic HBV infection and its clinicalprogression in male Han-Taiwaneserdquo PLoS ONE vol 9 no 6Article ID e99724 2014

[19] N Nishida H Sawai K Kashiwase et al ldquoNew susceptibilityand resistance HLA-DP alleles to HBV-related diseases identi-fied by a trans-ethnic association study in Asiardquo PLoS ONE vol9 no 2 Article ID e86449 2014

[20] C L Thio M Carrington D Marti et al ldquoClass II HLA allelesand hepatitis B virus persistence in African Americansrdquo Journalof Infectious Diseases vol 179 no 4 pp 1004ndash1006 1999

[21] AAAl-QahtaniM RAl-Anazi AAAbdo et al ldquoAssociationbetween HLA variations and chronic hepatitis B virus infectionin Saudi Arabian patientsrdquo PLoS ONE vol 9 no 1 Article IDe80445 2014

[22] K-C Lau C-W Lam C-Y Law et al ldquoNon-invasive screeningof HLA-DPA1 and HLA-DPB1 alleles for persistent hepatitisB virus infection susceptibility for vertical transmission andtoward a personalized approach for vaccination and treatmentrdquoClinica Chimica Acta vol 412 no 11-12 pp 952ndash957 2011

[23] Y-Y Xu J-Y Yu Y-W Zhong et al ldquoAssociation between thefrequency of class II HLA antigens and the susceptibility tointrauterine infection of hepatitis B virusrdquo International Journalof Biological Sciences vol 4 no 2 pp 111ndash115 2008


[24] M R Thursz D Kwiatkowski C E M Allsopp B M Green-wood H C Thomas and A V S Hill ldquoAssociation betweenan MHC class II allele and clearance of hepatitis B virus in thegambiardquoThe New England Journal of Medicine vol 332 no 16pp 1065ndash1069 1995

[25] T Hohler G Gerken A Notghi et al ldquoHLA-DRB1lowast1301 andlowast1302 protect against chronic hepatitis Brdquo Journal of Hepatologyvol 26 no 3 pp 503ndash507 1997

[26] S H Ahn K-HHan J Y Park et al ldquoAssociation between hep-atitis B virus infection andHLA-DR type in KoreardquoHepatologyvol 31 no 6 pp 1371ndash1373 2000

[27] L Wang X-P Wu W Zhang et al ldquoEvaluation of geneticsusceptibility loci for chronic hepatitis B in Chinese twoindependent case-control studiesrdquo PLoS ONE vol 6 no 3Article ID e17608 2011

[28] J Vermehren J Lotsch S Susser et al ldquoA common HLA-DPA1variant is associated with hepatitis B virus infection but fails todistinguish active from inactive Caucasian carriersrdquo PLoS ONEvol 7 no 3 Article ID e32605 2012

[29] A Mohamadkhani A Katoonizadeh and H Poustchi ldquoImm-une-regulatory events in the clearance of HBsAg in chronichepatitis B focuses on HLA-DPrdquo Middle East Journal of Diges-tive Diseases vol 7 no 1 pp 5ndash13 2015

[30] P Kummee P Tangkijvanich Y Poovorawan and N Hiran-karn ldquoAssociation of HLA-DRB1lowast13 and TNF-120572 gene polymor-phisms with clearance of chronic hepatitis B infection and riskof hepatocellular carcinoma inThai populationrdquo Journal of ViralHepatitis vol 14 no 12 pp 841ndash848 2007

[31] Z-H Yan Y Fan X-H Wang Q Mao G-H Deng and Y-MWang ldquoRelationship between HLA-DR gene polymorphismsand outcomes of hepatitis B viral infections a meta-analysisrdquoWorld Journal of Gastroenterology vol 18 no 24 pp 3119ndash31282012

[32] H-R Cheng C-J Liu T-C Tseng et al ldquoHost genetic factorsaffecting spontaneousHBsAg seroclearance in chronic hepatitisB patientsrdquo PLoS ONE vol 8 no 1 Article ID e53008 2013

[33] T R OrsquoBrien I Kohaar R M Pfeiffer et al ldquoRisk alleles forchronic hepatitis B are associated with decreased mRNAexpression of HLA-DPA1 and HLA-DPB1 in normal humanliverrdquo Genes and Immunity vol 12 no 6 pp 428ndash433 2011

[34] L Yu Y-J Cheng M-L Cheng et al ldquoQuantitative assessmentof common genetic variations in HLA-DP with hepatitis Bvirus infection clearance and hepatocellular carcinoma devel-opmentrdquo Scientific Reports vol 5 Article ID 14933 2015

[35] X Li W Liu H Wang et al ldquoThe influence of HLA allelesand HBV subgenotyes on the outcomes of HBV infections inNortheast Chinardquo Virus Research vol 163 no 1 pp 328ndash3332012

[36] A Almarri and J R Batchelor ldquoHLA and hepatitis B infectionrdquoThe Lancet vol 344 no 8931 pp 1194ndash1195 1994

[37] Y-F Wu L-Y Wang T-D Lee et al ldquoHLA phenotypes andoutcomes of hepatitis B virus infection in Taiwanrdquo Journal ofMedical Virology vol 72 no 1 pp 17ndash25 2004

[38] S L Zhang M Liu J Zhu and N L Chai ldquoPredominant Th-2immune response and chronic hepatitis B virus infectionrdquo ShijieHuaren Xiaohua Zazhi vol 7 pp 513ndash515 1999

[39] W N Chen and C J Oon ldquoMutation lsquohot spotrsquo in HLA classI-restricted T cell epitope on hepatitis B surface antigen inchronic carriers and hepatocellular carcinomardquo Biochemicaland Biophysical Research Communications vol 262 no 3 pp757ndash761 1999

[40] M Cotrina M Buti R Jardı et al ldquoStudy of HLA-II antigensin chronic hepatitis C and B and in acute hepatitis BrdquoGastroen-terologıa y Hepatologıa vol 20 no 3 pp 115ndash118 1997

[41] X Zhang J Jia J Dong et al ldquoHLA-DQ polymorphismswith HBV infection Different outcomes upon infection andprognosis to lamivudine therapyrdquo Journal of Viral Hepatitis vol21 no 7 pp 491ndash498 2014

[42] C Lin H Zou and S Wang ldquoHepatitis B e antigen sero-conversion is related with the function of dendritic cells inchronic hepatitis b virus infectionrdquo Gastroenterology Researchand Practice vol 2014 Article ID 413952 6 pages 2014

[43] J-F Wu C-H Chen R-P Hsieh et al ldquoHLA typing associatedwith hepatitis B E antigen seroconversion in children withchronic hepatitis B virus infection a long-term prospectivesibling cohort study in Taiwanrdquo Journal of Pediatrics vol 148no 5 pp 647ndash651 2006

[44] H Komatsu J Murakami A Inui T Tsunoda T Sogo andT Fujisawa ldquoAssociation between single-nucleotide polymor-phisms and early spontaneous hepatitis B virus e antigen sero-conversion in childrenrdquo BMC Research Notes vol 7 article 7892014

[45] P C Matthews J M Carlson A Beloukas et al ldquoHLA-A is apredictor of hepatitis B e antigen status in HIV-positive Africanadultsrdquo The Journal of Infectious Diseases vol 213 no 8 pp1248ndash1252 2016

[46] D K Jiang X P Ma X Wu et al ldquoGenetic variations inSTAT4C2HLA-DRB1 and HLA-DQ associated with risk ofhepatitis B virus-related liver cirrhosisrdquo Scientific Reports vol5 Article ID 16278 2015

[47] S Li J Qian Y Yang et al ldquoGWAS identifies novel susceptibilityloci on 6p2132 and 21q213 for hepatocellular carcinoma inchronic hepatitisB virus carriersrdquo PLoS Genetics vol 8 no 7Article ID e1002791 2012

[48] D-K Jiang J Sun G Cao et al ldquoGenetic variants in STAT4and HLA-DQ genes confer risk of hepatitis B virus-relatedhepatocellular carcinomardquo Nature Genetics vol 45 no 1 pp72ndash75 2013

[49] J Wen C Song D Jiang et al ldquoHepatitis B virus genotypemutations human leukocyte antigen polymorphisms and theirinteractions in hepatocellular carcinoma a multi-centre case-control studyrdquo Scientific Reports vol 5 Article ID 16489 2015

[50] J Zhang L Pan L Chen X Feng L Zhou and S Zheng ldquoNon-classical MHC-Ι genes in chronic hepatitis B and hepatocellularcarcinomardquo Immunogenetics vol 64 no 3 pp 251ndash258 2012

[51] L Doganay A Fejzullahu S Katrinli et al ldquoAssociation ofhuman leukocyte antigen DQB1 and DRB1 alleles with chronichepatitis Brdquo World Journal of Gastroenterology vol 20 no 25pp 8179ndash8186 2014

[52] Y Liao B Cai Y Li et al ldquoAssociation of HLA-DPDQ andSTAT4 polymorphisms with HBV infection outcomes and amini meta-analysisrdquo PLoS ONE vol 9 no 11 Article ID e1116772014

[53] N Pan J Qiu H Sun et al ldquoCombination of human leukocyteantigen and killer cell immunoglobulin-like receptor geneticbackground influences the onset age of hepatocellular carci-noma in male patients with hepatitis B virus infectionrdquo Clinicaland Developmental Immunology vol 2013 Article ID 874514 7pages 2013

[54] N PanW Jiang H Sun et al ldquoKIR andHLA loci are associatedwith hepatocellular carcinoma development in patients withhepatitis B virus infection a case-control studyrdquo PLoS ONE vol6 no 10 Article ID e25682 2011


[55] W P Brouwer M J Sonneveld F Tabak et al ldquoPolymorphismsof HLA-DP are associated with response to peginterferonin Caucasian patients with chronic hepatitis Brdquo AlimentaryPharmacology andTherapeutics vol 40 no 7 pp 811ndash818 2014

[56] Y-N Han J-L Yang S-G Zhen Q Tang and W ZhuldquoRelationship of human leukocyte antigen class II genes withthe susceptibility to hepatitis B virus infection and the responseto interferon in HBV-infected patientsrdquo World Journal of Gas-troenterology vol 11 no 36 pp 5721ndash5724 2005

[57] L Cheng X Sun S Tan et al ldquoEffect of HLA-DP and IL28Bgene polymorphisms on response to interferon treatment inhepatitis B e-antigen seropositive chronic hepatitis B patientsrdquoHepatology Research vol 44 no 9 pp 1000ndash1007 2014

[58] T-C Tseng M-L Yu C-J Liu et al ldquoEffect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis Bpatients receiving pegylated interferon-120572-2a therapyrdquo AntiviralTherapy vol 16 no 5 pp 629ndash637 2011

[59] T Hosaka F Suzuki M Kobayashi et al ldquoHLA-DP genes poly-morphisms associate with hepatitis B surface antigen kineticsand seroclearance during nucleot(s)ide analogue therapyrdquo LiverInternational vol 35 no 4 pp 1290ndash1302 2015

[60] Y-J Jin J H Shim Y-H Chung et al ldquoHLA-DRB1010101 alleleis closely associated with poor virological response to lamivu-dine therapy in patients with chronic hepatitis BrdquoDigestion vol84 no 1 pp 35ndash42 2011

[61] P Tangkijvanich S Chittmittraprap K Poovorawan et al ldquoArandomized clinical trial of peginterferon alpha-2b with orwithout entecavir in patients with HBeAg-negative chronichepatitis B role of host and viral factors associated withtreatment responserdquo Journal of Viral Hepatitis vol 23 no 6 pp427ndash438 2016

[62] Z-K Li J-J Nie J Li and H Zhuang ldquoThe effect of HLAon immunological response to hepatitis B vaccine in healthypeople a meta-analysisrdquo Vaccine vol 31 no 40 pp 4355ndash43612013

[63] GMert A SengulHCGul A Karakas andC P Eyigun ldquoTherole of human leukocyte antigen tissue groups in hepatitis Bvirus vaccination in Turkeyrdquo Journal of Microbiology Immunol-ogy and Infection vol 47 no 1 pp 9ndash14 2014

[64] J H Yoon S Shin JW In J Y Chang E Y Song and E Y RohldquoAssociation of HLA alleles with the responsiveness to hepatitisB virus vaccination in Korean infantsrdquo Vaccine vol 32 no 43pp 5638ndash5644 2014

[65] Y Zeng T Gao G Zhao et al ldquoGeneration of humanMHC (HLA-A11DR1) transgenic mice for vaccine evaluationrdquoHuman Vaccines amp Immunotherapeutics vol 19 2015

[66] S-H Hou J Hu Y Zhang Q-L Li and J-J Guo ldquoEffectsof interaction between genetic variants in human leukocyteantigen DQ and granulysin genes in Chinese Han subjectsinfected with hepatitis B virusrdquoMicrobiology and Immunologyvol 59 no 4 pp 209ndash218 2015

[67] D He S Tao S Guo et al ldquoInteraction of TLR-IFN and HLApolymorphisms on susceptibility of chronic HBV infection inSouthwest Han Chineserdquo Liver International vol 35 no 8 pp1941ndash1949 2015

[68] X Ji Q Zhang B Li et al ldquoImpacts of human leukocyteantigen DQ genetic polymorphisms and their interactions withhepatitis B virusmutations on the risks of viral persistence livercirrhosis and hepatocellular carcinomardquo Infection Genetics andEvolution vol 28 pp 201ndash209 2014

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

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Disease Markers


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


American subjects [15] It is therefore critical to identifythe associations of specific HLA allele variants with diseaseprogression and viral clearance in chronic HBV infectionsamong different ethnic groups

A deeper understanding of HLA polymorphism rele-vance in HBV infection outcome would help elucidate therole of HLA SNPs in the pathogenesis and clearance of HBVin different areas and ethnicities to improve strategies forthe prevention and treatment of chronic HBV infectionThisreview summarizes the reported associations of HLA poly-morphisms with susceptibility to HBV infection resolutiondisease progression and antivirus treatment efficacy andresponse to HBV vaccines

2 Associations of HLA Gene Variantswith Susceptibility and Persistence ofHBV Infection

Though several GWASs have revealed the association of genevariants in the HLA region with chronic HBV infectionthe susceptibility gene loci and potential mechanisms havenot been fully identified A comparative review showed thatHLA-DRB1lowast11lowast12 alleles andDQB1lowast0301 are associated withHBV persistence globally [14] A Chinese study by Zhu et al[16] identified four loci that independently drive chronicHBV infection including HLA-DP1205731 positions 84ndash87 HLA-DR1205731lowast13 sites 71 and rs400488 and HLA-C position 15In another study [17] after genotyping 140 SNPs withinthe HLA-DPDQ genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls 76 SNPsand 5 LD blocks were identified in HLA-DPDQ clustersindependent of each other which are significantly associatedwith HBV infection rs9277535 in HLA-DPB1 was found tobe the most significant locus Chang et al [18] found thatrs9277535 (HLA-DPB1) rs9276370 (HLA-DQA2) rs7756516and rs7453920 (HLA-DQB2) and rs9366816 nearHLA-DPA3are significantly associated with persistent HBV infectionespecially the ldquoT-Trdquo haplotype composed of rs7756516 andrs9276370 that is more prevalent in severe disease subgroupsand associated with nonsustained therapeutic response (119875 =00262) inmale TaiwanHanChinese individuals DQB1lowast0301and DQB1lowast0303 are correlated with continuous infection inXinjiang Uygur Chinese subjects [8]

A transethnic association analysis [19] performed amongAsian populations including Japanese Korean Hong Kongand Thai subjects revealed Asian-specific associations ofHLA-DPA1 and HLA-DPB1 alleleshaplotypes with HBVinfection and disease progression The latter study identifieda new risk allele HLA-DPB1lowast0901 and a new protective alleleDPB1lowast0201 in chronic HBV infection An American study[15] showed that the HLA-DPB1 31015840UTR 496GG genotypeconfers latent susceptibility to persistent HBV infection andis also associated with significantly higher levels of HLA-DP surface protein expression in healthy donors suggestingthat differences in HLA-DP expression may increase the riskfor persistent HBV infection in European Americans andAfrican Americans A prospective study [20] showed thatclass II alleles DQA1lowast0501 (119875 = 005) and DQB1lowast0301

(119875 = 001) the two-locus haplotype consisting of the lattertwo alleles and the three-locus haplotype DQA1lowast0501DQB1lowast0301 and DRB1lowast1102 (OR = 107 119875 = 001) aresignificantly associated with persistent HBV infection in anAfrican American cohort

In addition HBV persistence was shown to be associatedwith class II allelic homozygosity Interestingly three SNPsbelonging to the HLA-DQ region (rs2856718 rs7453920and rs9275572) shown to display increased susceptibilityto chronic HBV infection were detected in Saudi Arabianpatients [21] Meanwhile DRB1lowast08 and DRB1lowast09 alleleswhich are susceptible to HBV infection were found inBrazilian populations determined in young and male blooddonors [9] A study [22] identified 2 risk alleles in MHC locinamely HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535)using salivary DNA extracted with a modified protocol fromblood samples in Chinese patients This provides a newnoninvasive screening method for identifying risk loci

Furthermore HLA gene variants are also associatedwith susceptibility to vertical transmission Multiple factorsincluding HBV structure and DNA level placental barrierthe immune status of the mother and the genetic back-ground of the newborn infant determine the susceptibilityto intrauterine HBV infection Xu et al [23] assessed 15HLA-DR alleles and found HLA-DRB1lowast07 to be the onlyone associated with infant susceptibility to intrauterine HBVinfection

On the other hand gene polymorphisms of some HLAloci confer protective effects against persistentHBV infectionIt was shown that the HLA-DPA1 and HLA-DPB1 genesare significantly associated with protective effects againstCHB in Japanese Korean and other Asian populationsincluding Chinese and Thai individuals [19] Cross-sectionalstudies showed that HLA-DRB1lowast1301-02 are associated withprotection against persistent HBV infection in GambiaGermany and Korea [24ndash26] China has the highest HBVprevalence rate in the world with different ethnic popula-tionsWang et al [27] demonstrated that in two independentcase-control studies HLA-DP A alleles of both rs3077 andrs9277535 significantly decrease the risk for CHB in ChineseHan subjects while HLA-DP rs9277535 is associated withdecreased risk in Chinese Zhuang subjects In additionHLA-DQB1lowast0201 is HBV resistance gene in Xinjiang Uygurethnic groups of China [8] Although the most significantassociations were observed for HLA-DPA1 rs3077 and HLA-DPB1 rs9277535 A alleles (decreased risk for HBV infectionin Asian populations) only a highly significant associationof HLA-DPA1 rs3077 with HBV infection was observed inCaucasians [28]

3 Associations of HLA Gene Variantswith Spontaneous HBsAg Clearanceand HBV Eradication

Spontaneous HBsAg seroclearance occurs in a very smallproportion of patients with chronic HBV infection Themechanisms of spontaneous HBV clearance are determinedby the interactions between HBV and the host immuneresponse including innate and adaptive immune responses


























Competing Interests




References




64minus72from hep-










































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































Competing Interests




References




64minus72from hep-










































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































Competing Interests




References




64minus72from hep-










































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Competing Interests




References




64minus72from hep-










































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Clinical Relevance of HLA Gene Variants in ...downloads.hindawi.com/journals/jir/2016/9069375.pdf · gen (HLA) classes I and II alleles as well as non-HLA genes, in