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New loci associated with chronic hepatitis B virus infection in Han Chinese

Abstract

Chronic hepatitis B virus (HBV) infection is a challenging global health problem. To identify genetic loci involved in chronic HBV infection, we designed a three-phase genome-wide association study in Han Chinese populations. The discovery phase included 951 HBV carriers (cases) and 937 individuals who had naturally cleared HBV infection (controls) and was followed by independent replications with a total of 2,248 cases and 3,051 controls and additional replications with 1,982 HBV carriers and 2,622 controls from the general population. We identified two new loci associated with chronic HBV infection: rs3130542 at 6p21.33 (near HLA-C, odds ratio (OR) = 1.33, P = 9.49 × 10−14) and rs4821116 at 22q11.21 (in UBE2L3, OR = 0.82, P = 1.71 × 10−12). Additionally, we replicated the previously identified associations of HLA-DP and HLA-DQ variants at 6p21.32 with chronic HBV infection. These findings highlight the importance of HLA-C and UBE2L3 in the clearance of HBV infection in addition to HLA-DP and HLA-DQ.

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Figure 1: Regional plots of the three marker SNPs associated with chronic HBV infection.

References

  1. Liaw, Y.F. & Chu, C.M. Hepatitis B virus infection. Lancet 373, 582–592 (2009).

    Article  CAS  Google Scholar 

  2. Sener, S.F. Disease without borders. CA Cancer J. Clin. 55, 7–9 (2005).

    Article  Google Scholar 

  3. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    Article  Google Scholar 

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

    Article  Google Scholar 

  5. Beasley, R.P., Hwang, L.Y., Lin, C.C. & Chien, C.S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2, 1129–1133 (1981).

    Article  CAS  Google Scholar 

  6. He, Y.L., Zhao, Y.R., Zhang, S.L. & Lin, S.M. Host susceptibility to persistent hepatitis B virus infection. World J. Gastroenterol. 12, 4788–4793 (2006).

    Article  CAS  Google Scholar 

  7. Kamatani, Y. 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).

    Article  CAS  Google Scholar 

  8. Mbarek, H. et al. A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum. Mol. Genet. 20, 3884–3892 (2011).

    Article  CAS  Google Scholar 

  9. Nishida, N. et al. 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, e39175 (2012).

    Article  CAS  Google Scholar 

  10. Green, M.S. et al. Use of predictive value to adjust relative risk estimates biased by misclassification of outcome status. Am. J. Epidemiol. 117, 98–105 (1983).

    Article  CAS  Google Scholar 

  11. Han, Y. et al. Association of human leukocyte antigen–DRB1 alleles with chronic hepatitis B virus infection in the Han Chinese of Northeast China. Mol. Med. Rep. 5, 1347–1351 (2012).

    CAS  PubMed  Google Scholar 

  12. Li, X. et al. The influence of HLA alleles and HBV subgenotyes on the outcomes of HBV infections in Northeast China. Virus Res. 163, 328–333 (2012).

    Article  CAS  Google Scholar 

  13. Kummee, P. et al. Association of HLA-DRB1*13 and TNF-α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. J. Viral Hepat. 14, 841–848 (2007).

    CAS  PubMed  Google Scholar 

  14. Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

    Article  Google Scholar 

  15. Pique-Regi, R. et al. Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Res. 21, 447–455 (2011).

    Article  CAS  Google Scholar 

  16. An, P., Winkler, C., Guan, L., O'Brien, S.J. & Zeng, Z. A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese. J. Infect. Dis. 203, 943–947 (2011).

    Article  CAS  Google Scholar 

  17. Guo, X. et al. 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, 422–428 (2011).

    Article  CAS  Google Scholar 

  18. Hu, L. et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology 55, 1426–1431 (2012).

    Article  CAS  Google Scholar 

  19. Li, J. et al. 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, e24221 (2011).

    Article  CAS  Google Scholar 

  20. Thomas, R. et al. A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection. J. Virol. 86, 6979–6985 (2012).

    Article  Google Scholar 

  21. Vermehren, J. et al. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS ONE 7, e32605 (2012).

    Article  CAS  Google Scholar 

  22. Wang, L. et al. Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies. PLoS ONE 6, e17608 (2011).

    Article  CAS  Google Scholar 

  23. O'Brien, T.R. et al. 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, 428–433 (2011).

    Article  CAS  Google Scholar 

  24. Thio, C.L. et al. Class II HLA alleles and hepatitis B virus persistence in African Americans. J. Infect. Dis. 179, 1004–1006 (1999).

    Article  CAS  Google Scholar 

  25. Díaz, G. et al. Functional analysis of HLA-DP polymorphism: a crucial role for DPβ residues 9, 11, 35, 55, 56, 69 and 84–87 in T cell allorecognition and peptide binding. Int. Immunol. 15, 565–576 (2003).

    Article  Google Scholar 

  26. Chang, J.J. et al. Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy. J. Virol. 79, 3038–3051 (2005).

    Article  CAS  Google Scholar 

  27. Dubois, P.C. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42, 295–302 (2010).

    Article  CAS  Google Scholar 

  28. Fransen, K. et al. Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease. Hum. Mol. Genet. 19, 3482–3488 (2010).

    Article  CAS  Google Scholar 

  29. Hüffmeier, U. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat. Genet. 42, 996–999 (2010).

    Article  Google Scholar 

  30. Wang, S. et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immun. 13, 380–387 (2012).

    Article  CAS  Google Scholar 

  31. Zhernakova, A. et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 7, e1002004 (2011).

    Article  CAS  Google Scholar 

  32. Ballardini, G. et al. HLA-A,B,C, HLA-D/DR and HLA-D/DQ expression on unfixed liver biopsy sections from patients with chronic liver disease. Clin. Exp. Immunol. 70, 35–46 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, Y. et al. Hepatitis B virus core antigen epitopes presented by HLA-A2 single-chain trimers induce functional epitope-specific CD8+ T-cell responses in HLA-A2.1/Kb transgenic mice. Immunology 121, 105–112 (2007).

    Article  CAS  Google Scholar 

  34. Chen, W. et al. HBcAg-pulsed dendritic cell vaccine induces Th1 polarization and production of hepatitis B virus–specific cytotoxic T lymphocytes. Hepatol. Res. 39, 355–365 (2009).

    Article  CAS  Google Scholar 

  35. Chen, J.H. et al. Ubiquitin conjugation of hepatitis B virus core antigen DNA vaccine leads to enhanced cell-mediated immune response in BALB/c mice. Hepat. Mon. 11, 620–628 (2011).

    Article  Google Scholar 

  36. Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

    Article  CAS  Google Scholar 

  37. Moynihan, T.P. et al. Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3. Genomics 51, 124–127 (1998).

    Article  CAS  Google Scholar 

  38. Staib, F., Hussain, S.P., Hofseth, L.J., Wang, X.W. & Harris, C.C. TP53 and liver carcinogenesis. Hum. Mutat. 21, 201–216 (2003).

    Article  CAS  Google Scholar 

  39. Norton, P.A. et al. Activation of fibronectin gene expression by hepatitis B virus x antigen. J. Viral Hepat. 11, 332–341 (2004).

    Article  CAS  Google Scholar 

  40. Bertoletti, A. et al. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut 61, 1754–1764 (2012).

    Article  CAS  Google Scholar 

  41. Li, S. et al. GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers. PLoS Genet. 8, e1002791 (2012).

    Article  CAS  Google Scholar 

  42. Du, G. et al. Sero-epidemiological surveys of hepatitis B in different populations in Zhangjiagang city. Mod. Prev. Med. 23, 4560–4563 (2009).

    Google Scholar 

  43. Fang, Y. et al. Investigation of the serum markers of hepatitis B virus among 2378 physical examination takers in Shanghai. Occup. Health (Lond.) 4, 350–351 (2008).

    Google Scholar 

  44. Liang, X. et al. Epidemiological serosurvey of hepatitis B in China—declining HBV prevalence due to hepatitis B vaccination. Vaccine 27, 6550–6557 (2009).

    Article  Google Scholar 

  45. 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 

  46. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  47. Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all study subjects, research staff and students who participated in this work and Z. Wang (US National Cancer Institute) for statistical help with imputation. This work was funded by the National Key Basic Research Program (2013CB911400), the project supported by the National Science Foundation for Distinguished Young Scholars of China (81225020), the project supported by the State Key Program of National Natural Science of China (81230067), the Foundation for the Program for New Century Excellent Talents in University (NCET-10-0178), the Author of National Excellent Doctoral Dissertation (201081), the National Natural Science Foundation of China (30800946 and 81072344), the State Key Infectious Disease Project of China (2012ZX10002010 and 2012ZX10002016), the National Major Science & Technology Project (2011ZX10004-902), the National Science Fund for Creative Research Groups (30921006), the National Key Basic Research Program (2013CB910304), a China National High-Tech Research and Development Program grant (2012AA02A515), the Foundation for Distinguished Young Scholars of Jiangsu Province (BK2012042 and BK20130042) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

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Authors

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H.S. and Z.H. directed the study, obtained financial support and were responsible for study design, interpretation of the results and manuscript writing together with W.Z. and Y.S. Z.H. performed overall project management along with Y.L., G.J. and X.Z. and drafted the initial manuscript. J.D. performed statistical analyses along with Y.L. Y.L., M. Chu, J.W., Y.H. and K.X. were responsible for sample processing and managing the genotyping data. Y.Y. and Y.H. were responsible for subject recruitment and sample preparation for the Shanghai samples. X.Z., L.Z., G.D., Q.W., H.Y. and M. Cao were responsible for subject recruitment and sample preparation for the Zhangjiagang and Changzhou samples. X.Z., Y.Z. and J.W. were responsible for subject recruitment and sample preparation for the Taizhou samples. Jibin Liu, L.L. and K.X. were responsible for subject recruitment and sample preparation for the Nantong samples. L.W., G.Z. and Y.W. were responsible for subject recruitment and sample preparation for the Beijing samples. W.J., S.L. and J. Lu were responsible for subject recruitment and sample preparation for the Guangdong samples. Jianjun Liu provided technical and material support. All authors approved the final manuscript.

Corresponding authors

Correspondence to Zhibin Hu, Yongyong Shi, Weiping Zhou or Hongbing Shen.

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The authors declare no competing financial interests.

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Hu, Z., Liu, Y., Zhai, X. et al. New loci associated with chronic hepatitis B virus infection in Han Chinese. Nat Genet 45, 1499–1503 (2013). https://doi.org/10.1038/ng.2809

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