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A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians


Chronic hepatitis B is a serious infectious liver disease that often progresses to liver cirrhosis and hepatocellular carcinoma; however, clinical outcomes after viral exposure vary enormously among individuals1. Through a two-stage genome-wide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, we identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1. We validated these associations by genotyping two SNPs from the region in three additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 × 10−39 and 2.31 × 10−38, OR = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1*0202-DPB1*0501 and HLA-DPA1*0202-DPB1*0301, OR = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1*0103-DPB1*0402 and HLA-DPA1*0103-DPB1*0401, OR = 0.52 and 0.57, respectively). Our findings show that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus.

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Figure 1: Results from a two-stage genome-wide association study.
Figure 2: Case–control association results and linkage disequilibrium map of the MHC region.


  1. Pungpapong, S., Kim, W. & Poterucha, J. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin. Proc. 82, 967–975 (2007).

    Article  CAS  Google Scholar 

  2. Custer, B. et al. Global epidemiology of hepatitis B virus. J. Clin. Gastroenterol. 38, S158–S168 (2004).

    Article  Google Scholar 

  3. Lai, C.L., Ratziu, V., Yuen, M.F. & Poynard, T. Viral hepatitis B. Lancet 362, 2089–2094 (2003).

    Article  CAS  Google Scholar 

  4. Kobayashi, M. et al. Viral genotypes and response to interferon in patients with acute prolonged hepatitis B virus infection of adulthood in Japan. J. Med. Virol. 68, 522–528 (2002).

    Article  CAS  Google Scholar 

  5. Laskus, T. et al. Prevalence of markers of hepatitis viruses in out-patient alcoholics. J. Hepatol. 15, 174–178 (1992).

    Article  CAS  Google Scholar 

  6. Sheen, I., Liaw, Y., Lin, D. & Chu, C. Role of hepatitis C and delta viruses in the termination of chronic hepatitis B surface antigen carrier state: a multivariate analysis in a longitudinal follow-up study. J. Infect. Dis. 170, 358–361 (1994).

    Article  CAS  Google Scholar 

  7. Lin, T. et al. Hepatitis B virus markers in Chinese twins. Anticancer Res. 9, 737–741 (1989).

    CAS  PubMed  Google Scholar 

  8. Ben-Ari, Z. et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am. J. Gastroenterol. 98, 144–150 (2003).

    Article  CAS  Google Scholar 

  9. Thursz, M.R. et al. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N. Engl. J. Med. 332, 1065–1069 (1995).

    Article  CAS  Google Scholar 

  10. Bellamy, R. et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J. Infect. Dis. 179, 721–724 (1999).

    Article  CAS  Google Scholar 

  11. Deng, G. et al. Association of estrogen receptor polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 40, 318–326 (2004).

    Article  CAS  Google Scholar 

  12. Singh, R., Kaul, R., Kaul, A. & Khan, K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World J. Gastroenterol. 13, 1770–1787 (2007).

    Article  CAS  Google Scholar 

  13. Hohler, T. et al. HLA-DRB1* 1301 and* 1302 protect against chronic hepatitis B. J. Hepatol. 26, 503–507 (1997).

    Article  CAS  Google Scholar 

  14. Ahn, S.H. et al. Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology 31, 1371–1373 (2000).

    Article  CAS  Google Scholar 

  15. Frodsham, A. Host genetics and the outcome of hepatitis B viral infection. Transpl. Immunol. 14, 183–186 (2005).

    Article  CAS  Google Scholar 

  16. Frodsham, A. et al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc. Natl. Acad. Sci. USA 103, 9148–9153 (2006).

    Article  CAS  Google Scholar 

  17. Jung, M. et al. Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection. J. Virol. 69, 3358–3368 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Fontenot, A., Torres, M., Marshall, W., Newman, L. & Kotzin, B. Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc. Natl. Acad. Sci. USA 97, 12717–12722 (2000).

    Article  CAS  Google Scholar 

  19. Mineta, M. et al. Contribution of HLA class I and class II alleles to the regulation of antibody production to hepatitis B surface antigen in humans. Int. Immunol. 8, 525–531 (1996).

    Article  CAS  Google Scholar 

  20. Nakamura, Y. The BioBank Japan project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).

    PubMed  Google Scholar 

  21. Saito, A. & Kamatani, N. Strategies for genome-wide association studies: optimization of study designs by the stepwise focusing method. J. Hum. Genet. 47, 360–365 (2002).

    Article  CAS  Google Scholar 

  22. van der Zwan, A., Griffith, B., Rozemuller, E., Williams, T. & Tilanus, M.G.J. IHWG Technical Manual Genomic Analysis of the Human MHC: DNA-Based Typing for HLA Alleles and Linked Polymorphisms (ed. Tilanus, M.G.J.) (Seattle, Washington, International Histocompatibility Working Group, 2002).

  23. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  24. Barrett, J., Fry, B., Maller, J. & Daly, M. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  25. Schaid, D.J., Rowland, C.M., Tines, D.E., Jacobson, R.M. & Poland, G.A. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet. 70, 425–434 (2002).

    Article  Google Scholar 

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We thank K. Tokunaga for useful advice of on HLA-DP genotyping and interpretation, and technical staff of Laboratory for Genotyping Development at RIKEN for SNP genotyping at the first and second stages of the GWAS. We are also grateful to members of Hiroshima Liver Study Group and The Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.

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Authors and Affiliations



Y.N. conceived the study; Y.N., Y.K., Y.D., M.K. and K.M. designed the study; Y.K., S.W., H.O. and N.H. performed genotyping; Y.K., T.T., M.K., N.K., Y.N. and K.M. wrote the manuscript; T.K., A.T., T.T. and N.K. performed data analysis at the genome-wide phase; Y.N., K.M. and M.K. managed DNA samples belong to BioBankJapan; K.C. and H.K. managed second replication samples; W.C., A.P. and T.S. managed third replication samples in Thailand; Y.K. summarized the whole results; Y.N. obtained funding for the study.

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Correspondence to Yusuke Nakamura.

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Kamatani, Y., Wattanapokayakit, S., Ochi, H. et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 41, 591–595 (2009).

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