Premium
Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome‐wide association study
Author(s) -
Lee MeiHsuan,
Huang YuHan,
Chen HsuanYu,
Khor SeikSoon,
Chang YaHsuan,
Lin YuJu,
Jen ChinLan,
Lu ShengNan,
Yang HwaiI,
Nishida Nao,
Sugiyama Masaya,
Mizokami Masashi,
Yuan Yong,
L'Italien Gibert,
Tokunaga Katsushi,
Chen ChienJen
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29531
Subject(s) - hepatocellular carcinoma , genotype , virology , hepatitis c virus , hepatitis b virus , genome , hepatitis virus , biology , virus , genome wide association study , medicine , gene , genetics , single nucleotide polymorphism
We conducted a genome‐wide association study to discover genetic variants associated with hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non‐HCC controls using the Axiom‐CHB genome‐wide array. After identifying single‐nucleotide polymorphism clusters located in the human leukocyte antigen ( HLA ) region which were potentially associated with HCC, HLA‐DQB1 genotyping was performed to analyze 994 anti‐HCV seropositives collected in the period 1991‐2013 in a community‐based cohort for evaluating long‐term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single‐nucleotide polymorphisms in the proximity of HLA‐DQB1 were associated with HCC ( P < 8.7 × 10 −8 ) in the genome‐wide association study. Long‐term follow‐up showed a significant association with HLA‐DQB1*03:01 and DQB1*06:02 ( P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30‐0.68) and 2.11 (1.34‐3.34) for DQB1*03:01 and DQB1*06:02 , respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non‐1 genotypes. HLA imputation analyses revealed that HLA‐DRB1*15:01 , which is in linkage disequilibrium with DQB1*06:02 , also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31‐2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA‐DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA‐DQB1 on the risk of HCC. (H epatology 2018;67:651‐661).