Genome-Wide Association Study Confirming Association of HLA-DP with Protection against Chronic Hepatitis B and Viral Clearance in Japanese and Korean

Nao Nishida, Hiromi Sawai, Kentaro Matsuura, Masaya Sugiyama, Sang Hoon Ahn, Jun Yong Park, Shuhei Hige, Jong-Hon Kang, Kazuyuki Suzuki, Masayuki Kurosaki, Yasuhiro Asahina, Satoshi Mochida, Masaaki Watanabe, Eiji Tanaka, Masao Honda, Shuichi Kaneko, Etsuro Orito, Yoshito Itoh, Eiji Mita, Akihiro Tamori, Yoshikazu Murawaki, Yoichi Hiasa, Isao Sakaida, Masaaki Korenaga, Keisuke Hino, Tatsuya Ide, Minae Kawashima, Yoriko Mawatari, Megumi Sageshima, Yuko Ogasawara, Asako Koike, Namiki Izumi, Kwang-Hyub Han, Yasuhito Tanaka, Katsushi Tokunaga, Masashi Mizokami

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta) = 1.89×10⁻¹² for rs3077 and P(meta) = 9.69×10⁻¹⁰ for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta) = 4.40×10⁻¹⁹ for rs3077 and P(meta) = 1.28×10⁻¹⁵ for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.