Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma

Hiromi Sawai,Masao Honda,Yong Poovorawan,Shoichiro Tsugane,Tatsuo Kanda,Osamu Yokosuka,Yuichiro Eguchi,Sohji Nishina,Masaya Sugiyama,Nao Nishida,Shinya Nagaoka,Nawarat Posuwan,Masashi Mizokami,Kazumoto Murata,Man‐Fung Yuen ,Wai‐Kay Seto ,Seik‐Soon Khor ,Kazuhiko Koike,Koji Ogawa,Kayoko Yamada,Keisuke Hino,Akihiro Matsumoto,Satoshi Oeda,Yuji Kondo,Isao Sakaida,Masayuki Kurosaki,Kazuhide Yamamoto,Hiroshi Yatsuhashi,Satoshi Mochida,Naoya Sakamoto,Yoshito Itoh,Natsumi Baba,Akinobu Taketomi,Jong-Hon Kang,Akihiro Tamori,Eiji Tanaka,Norie Sawada,Namiki Izumi,Moto Fukai,Katsushi Tokunaga

doi:10.1038/s41598-018-26217-7

Abstract

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10−4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A*33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Highlights

We have performed a genome-wide association study (GWAS) including 473 Japanese hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations
Recent genome-wide association studies (GWAS) of chronic HBV carriers with or without HCC in Chinese populations reported that one SNP in KIF1B, two SNPs in Human leucocyte antigen (HLA)-DQA1/ DRB1 and GRIK1, and two SNPs in STAT4 and HLA-DQ were associated with disease progression to HCC8–10
These results suggested that HBV-related HCC could be associated with SNPs located in the HLA region, associations did not reach the genome-wide significance level

Summary

Introduction

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. Recent genome-wide association studies (GWAS) of chronic HBV carriers with or without HCC in Chinese populations reported that one SNP (rs17401966) in KIF1B, two SNPs (rs9272105 and rs455804) in HLA-DQA1/ DRB1 and GRIK1, and two SNPs (rs7574865 and rs9275319) in STAT4 and HLA-DQ were associated with disease progression to HCC8–10. The study by Zhang et al.[10] used 2,310 cases and 1,789 controls of Chinese ancestry and identified one intronic SNP in KIF1B associated with HBV-related HCC This result, was not replicated in several other populations[11,12]).

Methods

Results

Conclusion