A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population

Hamdi Mbarek, Hidenori Ochi, Yuji Urabe, Vinod Kumar, Michiaki Kubo, Naoya Hosono, Atsushi Takahashi, Yoichiro Kamatani, Daiki Miki, Hiromi Abe, Tatsuhiko Tsunoda, Naoyuki Kamatani, Kazuaki Chayama, Yusuke Nakamura, Koichi Matsuda

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10(-5). We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10(-28) and 3.99 × 10(-37)). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10(-21)- 2.38 × 10(-30)). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

Original languageEnglish
Pages (from-to)3884-92
Number of pages9
JournalHuman Molecular Genetics
Volume20
Issue number19
DOIs
Publication statusPublished - 1 Oct 2011

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Keywords

  • Asian Continental Ancestry Group
  • Case-Control Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HLA-DP Antigens
  • HLA-DQ Antigens
  • Hepatitis B, Chronic
  • Humans
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Journal Article
  • Research Support, Non-U.S. Gov't

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