Human Leukocyte Antigen Variants and Risk of Hepatocellular Carcinoma Modified by HCV Genotypes: A Genome-wide Association Study

Abstract

Background & aims: We conducted a genome-wide association study (GWAS) to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

Methods: We genotyped 502 HCC cases and 749 non-HCC controls by using the Axiom^TM-CHB genome-wide array. After identifying single nucleotide polymorphism (SNP) cluster located in the human leukocyte antigen region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period of 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 (HRs) and 95% confidence intervals (CIs) of HLA genotypes for determining the aforementioned HCC risk.

Results: Eight SNPs in the proximity of HLA-DQB1 were associated with HCC (p < 8.7 × 10⁻⁸) in GWAS. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (p < 0.05). The adjusted HRs 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% CI = 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primary protective and susceptible variants, respectively.

Conclusions: HLA-DQB1 was independently associated with HCC. HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. This article is protected by copyright. All rights reserved.

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