Skip to main content

Advertisement

SpringerLink
Log in

Association of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes

  • Invited Review
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Hepatitis B virus (HBV) infection affects more than 2 billion people throughout the world. Among them, more than 240 million have chronic infection. Every year, 0.5–1.2 million people die of chronic hepatitis B virus infection (CHBVI), and approximately 60 % of liver cancers are related to CHBI and subsequent liver cirrhosis (LC). These HBVI-related diseases impose a considerable economic burden as well as morbidity on patients, families, and society. Family and twin studies have indicated that the host genetic constitution greatly influences the clinical outcomes of HBV infection. During the past several years, genome-wide association studies (GWAS) have identified susceptibility variants for various HBVI-related diseases. Of these variants, SNPs rs3077 and rs9277535 in HLA-DP on chromosome 6 show the strongest evidence for association with CHBVI and with viral clearance. However, whether there exists an association between HLA-DP variants and the progression of CHBVI remains to be determined. Thus, further study should focus not only on identifying more variants in HLA-DP that are associated with various HBVI-related diseases but also on characterizing any newly discovered functional variants at the molecular level. Further, given the complexity of CHBV infection and its progression, gene–gene and gene–environment interactions should also be taken into consideration. Moreover, because both smoking and alcohol affect HBV infection and progression, it is important to understand how these factors interact with genetics to influence HBV-related diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM (2000) Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology 31(6):1371–1373. doi:10.1053/jhep.2000.7988

    Article  CAS  PubMed  Google Scholar 

  • Al-Qahtani AA, Al-Anazi MR, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA, Al-Ashgar HI, Khalaf NZ, Eldali AM, Viswan NA, Al-Ahdal MN (2014) Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients. PLoS ONE 9(1):e80445. doi:10.1371/journal.pone.0080445

    Article  PubMed Central  PubMed  Google Scholar 

  • An P, Winkler C, Guan L, O’Brien SJ, Zeng Z, Consortium HBVS (2011) A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese. J Infect Dis 203(7):943–947. doi:10.1093/infdis/jiq154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV (1999) Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 179(3):721–724. doi:10.1086/314614

    Article  CAS  PubMed  Google Scholar 

  • Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T (2003) Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol 98(1):144–150. doi:10.1111/j.1572-0241.2003.07179.x

    Article  CAS  PubMed  Google Scholar 

  • Chen CJ, Wang LY, Yu MW (2000) Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 15(Suppl):E3–E6

    Article  PubMed  Google Scholar 

  • Chen JD, Yang HI, Iloeje UH, You SL, Lu SN, Wang LY, Su J, Sun CA, Liaw YF, Chen CJ, Risk Evaluation of Viral Load E, Associated Liver Disease/Cancer in HBVSG (2010) Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology 138(5):1747–1754. doi:10.1053/j.gastro.2010.01.042

    Article  PubMed  Google Scholar 

  • Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F (2004) Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 40(2):318–326. doi:10.1002/hep.20318

    Article  CAS  PubMed  Google Scholar 

  • Diaz G, Amicosante M, Jaraquemada D, Butler RH, Guillen MV, Sanchez M, Nombela C, Arroyo J (2003) Functional analysis of HLA-DP polymorphism: a crucial role for DPbeta residues 9, 11, 35, 55, 56, 69 and 84-87 in T cell allorecognition and peptide binding. Int Immunol 15(5):565–576

    Article  CAS  PubMed  Google Scholar 

  • Frodsham AJ (2005) Host genetics and the outcome of hepatitis B viral infection. Transpl Immunol 14(3–4):183–186. doi:10.1016/j.trim.2005.03.006

    Article  CAS  PubMed  Google Scholar 

  • Ganem D, Prince AM (2004) Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 350(11):1118–1129. doi:10.1056/NEJMra031087

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Zhang Y, Li J, Ma J, Wei Z, Tan W, O’Brien SJ (2011) Strong influence of human leukocyte antigen (HLA)-DP gene variants on development of persistent chronic hepatitis B virus carriers in the Han Chinese population. Hepatology 53(2):422–428. doi:10.1002/hep.24048

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gust ID (1996) Epidemiology of hepatitis B infection in the Western Pacific and South East Asia. Gut 38(Suppl 2):S18–S23

    Article  PubMed Central  PubMed  Google Scholar 

  • Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6(10):776–788. doi:10.1038/nrc1994

    Article  CAS  PubMed  Google Scholar 

  • Hsieh CC, Tzonou A, Zavitsanos X, Kaklamani E, Lan SJ, Trichopoulos D (1992) Age at first establishment of chronic hepatitis B virus infection and hepatocellular carcinoma risk. A birth order study. Am J Epidemiol 136(9):1115–1121

    CAS  PubMed  Google Scholar 

  • Hu L, Zhai X, Liu J, Chu M, Pan S, Jiang J, Zhang Y, Wang H, Chen J, Shen H, Hu Z (2012) Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology 55(5):1426–1431. doi:10.1002/hep.24799

    Article  CAS  PubMed  Google Scholar 

  • Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, Zhu L, Yang Y, Liu J, Chu M, Wen J, Xie K, Du G, Wang Q, Zhou Y, Cao M, Liu L, He Y, Wang Y, Zhou G, Jia W, Lu J, Li S, Liu J, Yang H, Shi Y, Zhou W, Shen H (2013) New loci associated with chronic hepatitis B virus infection in Han Chinese. Nat Genet 45(12):1499–1503. doi:10.1038/ng.2809

    Article  CAS  PubMed  Google Scholar 

  • Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, Kubo M, Tsunoda T, Kamatani N, Kumada H, Puseenam A, Sura T, Daigo Y, Chayama K, Chantratita W, Nakamura Y, Matsuda K (2009) A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 41(5):591–595. doi:10.1038/ng.348

    Article  CAS  PubMed  Google Scholar 

  • Kim YJ, Kim HY, Lee JH, Yu SJ, Yoon JH, Lee HS, Kim CY, Cheong JY, Cho SW, Park NH, Park BL, Namgoong S, Kim LH, Cheong HS, Shin HD (2013) A genome-wide association study identified new variants associated with the risk of chronic hepatitis B. Hum Mol Genet 22(20):4233–4238. doi:10.1093/hmg/ddt266

    Article  CAS  PubMed  Google Scholar 

  • Lai CL, Ratziu V, Yuen MF, Poynard T (2003) Viral hepatitis B. Lancet 362(9401):2089–2094. doi:10.1016/S0140-6736(03)15108-2

    Article  CAS  PubMed  Google Scholar 

  • Li J, Yang D, He Y, Wang M, Wen Z, Liu L, Yao J, Matsuda K, Nakamura Y, Yu J, Jiang X, Sun S, Liu Q, Jiang X, Song Q, Chen M, Yang H, Tang F, Hu X, Wang J, Chang Y, He X, Chen Y, Lin J (2011) Associations of HLA-DP variants with hepatitis B virus infection in southern and northern Han Chinese populations: a multicenter case–control study. PLoS ONE 6(8):e24221. doi:10.1371/journal.pone.0024221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li S, Qian J, Yang Y, Zhao W, Dai J, Bei JX, Foo JN, McLaren PJ, Li Z, Yang J, Shen F, Liu L, Yang J, Li S, Pan S, Wang Y, Li W, Zhai X, Zhou B, Shi L, Chen X, Chu M, Yan Y, Wang J, Cheng S, Shen J, Jia W, Liu J, Yang J, Wen Z, Li A, Zhang Y, Zhang G, Luo X, Qin H, Chen M, Wang H, Jin L, Lin D, Shen H, He L, de Bakker PI, Wang H, Zeng YX, Wu M, Hu Z, Shi Y, Liu J, Zhou W (2012) GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers. PLoS Genet 8(7):e1002791. doi:10.1371/journal.pgen.1002791

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liaw YF, Chu CM (2009) Hepatitis B virus infection. Lancet 373(9663):582–592. doi:10.1016/S0140-6736(09)60207-5

    Article  CAS  PubMed  Google Scholar 

  • Lin TM, Chen CJ, Wu MM, Yang CS, Chen JS, Lin CC, Kwang TY, Hsu ST, Lin SY, Hsu LC (1989) Hepatitis B virus markers in Chinese twins. Anticancer Res 9(3):737–741

    CAS  PubMed  Google Scholar 

  • Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362(9399):1907–1917. doi:10.1016/S0140-6736(03)14964-1

    Article  PubMed  Google Scholar 

  • Lok AS (2002) Chronic hepatitis B. N Engl J Med 346(22):1682–1683. doi:10.1056/NEJM200205303462202

    Article  PubMed  Google Scholar 

  • Lu J, Xu A, Wang J, Zhang L, Song L, Li R, Zhang S, Zhuang G, Lu M (2013) Direct economic burden of hepatitis B virus related diseases: evidence from Shandong. China. BMC Health Serv Res 13:37. doi:10.1186/1472-6963-13-37

    Article  Google Scholar 

  • Mahoney FJ (1999) Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 12(2):351–366

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N, Takahashi A, Kamatani Y, Miki D, Abe H, Tsunoda T, Kamatani N, Chayama K, Nakamura Y, Matsuda K (2011) A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum Mol Genet 20(19):3884–3892. doi:10.1093/hmg/ddr301

    Article  CAS  PubMed  Google Scholar 

  • Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park JY, Hige S, Kang JH, Suzuki K, Kurosaki M, Asahina Y, Mochida S, Watanabe M, Tanaka E, Honda M, Kaneko S, Orito E, Itoh Y, Mita E, Tamori A, Murawaki Y, Hiasa Y, Sakaida I, Korenaga M, Hino K, Ide T, Kawashima M, Mawatari Y, Sageshima M, Ogasawara Y, Koike A, Izumi N, Han KH, Tanaka Y, Tokunaga K, Mizokami M (2012) Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS ONE 7(6):e39175. doi:10.1371/journal.pone.0039175

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Brien TR, Kohaar I, Pfeiffer RM, Maeder D, Yeager M, Schadt EE, Prokunina-Olsson L (2011) Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver. Genes Immun 12(6):428–433. doi:10.1038/gene.2011.11

    Article  PubMed Central  PubMed  Google Scholar 

  • Ohnishi K, Terabayashi H, Unuma T, Takahashi A, Okuda K (1987) Effects of habitual alcohol intake and cigarette smoking on the development of hepatocellular carcinoma. Alcohol Clin Exp Res 11(1):45–48

    Article  CAS  PubMed  Google Scholar 

  • Pieters J (2000) MHC class II-restricted antigen processing and presentation. Adv Immunol 75:159–208

    Article  CAS  PubMed  Google Scholar 

  • Seto WK, Wong DK, Kopaniszen M, Proitsi P, Sham PC, Hung IF, Fung J, Lai CL, Yuen MF (2013) HLA-DP and IL28B polymorphisms: influence of host genome on hepatitis B surface antigen seroclearance in chronic hepatitis B. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 56(12):1695–1703. doi:10.1093/cid/cit121

    Article  CAS  Google Scholar 

  • Thio CL, Carrington M, Marti D, O’Brien SJ, Vlahov D, Nelson KE, Astemborski J, Thomas DL (1999) Class II HLA alleles and hepatitis B virus persistence in African Americans. J Infect Dis 179(4):1004–1006. doi:10.1086/314684

    Article  CAS  PubMed  Google Scholar 

  • Thio CL, Thomas DL, Carrington M (2000) Chronic viral hepatitis and the human genome. Hepatology 31(4):819–827. doi:10.1053/he.2000.4316

    Article  CAS  PubMed  Google Scholar 

  • Thio CL, Mosbruger TL, Kaslow RA, Karp CL, Strathdee SA, Vlahov D, O’Brien SJ, Astemborski J, Thomas DL (2004) Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection. J Virol 78(20):11258–11262. doi:10.1128/JVI.78.20.11258-11262.2004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas HC, Foster GR, Sumiya M, McIntosh D, Jack DL, Turner MW, Summerfield JA (1996) Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection. Lancet 348(9039):1417–1419

    Article  CAS  PubMed  Google Scholar 

  • Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 332(16):1065–1069. doi:10.1056/NEJM199504203321604

    Article  CAS  PubMed  Google Scholar 

  • Vermehren J, Lotsch J, Susser S, Wicker S, Berger A, Zeuzem S, Sarrazin C, Doehring A (2012) A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS ONE 7(3):e32605. doi:10.1371/journal.pone.0032605

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang L, Wu XP, Zhang W, Zhu DH, Wang Y, Li YP, Tian Y, Li RC, Li Z, Zhu X, Li JH, Cai J, Liu L, Miao XP, Liu Y, Li H (2011) Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case–control studies. PLoS ONE 6(3):e17608. doi:10.1371/journal.pone.0017608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678. doi:10.1038/nature05911

    Article  Google Scholar 

  • Wong DK, Watanabe T, Tanaka Y, Seto WK, Lee CK, Fung J, Lin CK, Huang FY, Lai CL, Yuen MF (2013) Role of HLA-DP polymorphisms on chronicity and disease activity of hepatitis B infection in Southern Chinese. PLoS ONE 8(6):e66920. doi:10.1371/journal.pone.0066920

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wu TW, Chu CC, Ho TY, Chang Liao HW, Lin SK, Lin M, Lin HH, Wang LY (2013) Responses to booster hepatitis B vaccination are significantly correlated with genotypes of human leukocyte antigen (HLA)-DPB1 in neonatally vaccinated adolescents. Hum Genet 132(10):1131–1139. doi:10.1007/s00439-013-1320-5

    Article  CAS  PubMed  Google Scholar 

  • Yan Z, Tan S, Dan Y, Sun X, Deng G, Wang Y (2012) Relationship between HLA-DP gene polymorphisms and clearance of chronic hepatitis B virus infections: case–control study and meta-analysis. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 12(6):1222–1228. doi:10.1016/j.meegid.2012.03.026

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, Ma F, Huang W, Yu L, Yue W, Wang Z, Li P, Zhang Y, Liang R, Wei Z, Cui Y, Xie W, Cai M, Yu X, Yuan Y, Xia X, Zhang X, Yang H, Qiu W, Yang J, Gong F, Chen M, Shen H, Lin D, Zeng YX, He F, Zhou G (2010) Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet 42(9):755–758. doi:10.1038/ng.638

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Pan X, Shu X, Cao H, Chen L, Zou Y, Deng H, Li G, Xu Q (2013) Relationship between MIF-173 G/C polymorphism and susceptibility to chronic hepatitis B and HBV-induced liver cirrhosis. Cell Immunol 282(2):113–116. doi:10.1016/j.cellimm.2013.04.013

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The preparation of this review was supported in part by the Ministry of Science and Technology of China (2012AA020405) and the National Natural Science Foundation of China grant 81273223.

Conflict of interest

The authors declare that they have no conflict of interest on this report.

Author information

Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China

    Xianzhong Jiang, Yunlong Ma, Wenyan Cui & Ming D. Li

  2. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 450 Ray C Hunt Drive, G-170, Charlottesville, VA, 22903, USA

    Ming D. Li

Authors
  1. Xianzhong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunlong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenyan Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming D. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming D. Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, X., Ma, Y., Cui, W. et al. Association of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes. Amino Acids 46, 1819–1826 (2014). https://doi.org/10.1007/s00726-014-1767-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-014-1767-2

Keywords

Search

Navigation