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. (Hepatology 2018;67:651‐661).

中文翻译：

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HCV 基因型修饰的人类白细胞抗原变体和肝细胞癌风险：一项全基因组关联研究

我们进行了一项全基因组关联研究，以发现与丙型肝炎病毒 (HCV) 相关肝细胞癌 (HCC) 相关的遗传变异。我们使用 Axiom-CHB 全基因组阵列对 502 例 HCC 病例和 749 例非 HCC 对照进行基因分型。在识别出可能与 HCC 相关的人类白细胞抗原 (HLA) 区域的单核苷酸多态性簇后，进行 HLA-DQB1 基因分型以分析 1991-2013 年期间在基于社区的队列中收集的 994 例抗 HCV 血清阳性用于评估 HLA 变异体的长期可预测性，以确定 HCC 的风险。Cox 比例风险模型用于估计 HLA 基因型的风险比和 95% 置信区间，以确定上述 HCC 风险。在全基因组关联研究中，HLA-DQB1 附近的八个单核苷酸多态性与 HCC 相关（P < 8.7 × 10-8）。长期随访显示与 HLA-DQB1*03:01 和 DQB1*06:02 显着相关（P < 0.05）。对于 DQB1*03:01 和 DQB1*06:02，与 HCC 相关的调整后风险比分别为 0.45 (0.30-0.68) 和 2.11 (1.34-3.34)。按 HCV 基因型分层后，DQB1*03:01 仅对 HCV 基因型 1 的患者显示出保护作用，而 DQB1*06:02 仅对非 HCV 基因型的患者赋予 HCC 风险。HLA 插补分析显示，与 DQB1*06:02 连锁不平衡的 HLA-DRB1*15:01 也增加了 HCC 的风险（优势比，1.96；95% 置信区间，1.31-2.93）。单倍型分析支持 DQB1*03:01 和 DQB1*06：02 分别是主要的保护性和易感变体。结论：HLA-DQB1 与 HCC 独立相关；HCV 基因型改变了 HLA-DQB1 对 HCC 风险的影响。（肝病学 2018 年；67：651-661）。