Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean.
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.
Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan. nishida-75@umin.ac.jp
Nao
N
Nishida
Hiromi
H
Sawai
Kentaro
K
Matsuura
Masaya
M
Sugiyama
Sang Hoon
SH
Ahn
Jun Yong
JY
Park
Shuhei
S
Hige
Jong-Hon
JH
Kang
Kazuyuki
K
Suzuki
Masayuki
M
Kurosaki
Yasuhiro
Y
Asahina
Satoshi
S
Mochida
Masaaki
M
Watanabe
Eiji
E
Tanaka
Masao
M
Honda
Shuichi
S
Kaneko
Etsuro
E
Orito
Yoshito
Y
Itoh
Eiji
E
Mita
Akihiro
A
Tamori
Yoshikazu
Y
Murawaki
Yoichi
Y
Hiasa
Isao
I
Sakaida
Masaaki
M
Korenaga
Keisuke
K
Hino
Tatsuya
T
Ide
Minae
M
Kawashima
Yoriko
Y
Mawatari
Megumi
M
Sageshima
Yuko
Y
Ogasawara
Asako
A
Koike
Namiki
N
Izumi
Kwang-Hyub
KH
Han
Yasuhito
Y
Tanaka
Katsushi
K
Tokunaga
Masashi
M
Mizokami
D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006682:HLA-DP Antigens / Q000235:genetics / Q000276:immunology*; D059867:HLA-DP alpha-Chains / Q000235:genetics; D059868:HLA-DP beta-Chains / Q000235:genetics; D006239:Haplotypes; D006509:Hepatitis B / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D006801:Humans; D007564:Japan; D007723:Korea; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D025341:Principal Component Analysis; D012074:Remission Induction
D006682:HLA-DP Antigens; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen