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

Abstract

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.

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Acknowledgements

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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Contributions

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.

Corresponding author

Correspondence to Yusuke Nakamura.

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Supplementary Figures 1 and 2 and Supplementary Tables 1–6 (PDF 394 kb)

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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). https://doi.org/10.1038/ng.348

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