Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese.
Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese.
复制标题
MHC 区域精细定位识别出与中国汉族 HBV 相关肝细胞癌相关的新变异
DOI：
10.2147/jhc.s321919
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发表时间：
2021
影响因子：
4.1
通讯作者：
Jiang D
中科院分区：
文献类型：
--
作者：
Mai H;Chen J;Chen H;Liu Z;Huang G;Wang J;Xiao Q;Ren W;Zhou B;Hou J;Jiang D
全基因组关联研究确定了主要组织相容性复合体区域中与B型肝炎病毒（HBV）相关的肝细胞癌（HCC）的易感性位点。然而，HBV相关的HCC发病机制的致病变异仍然难以捉摸。方法对1,161例HBV相关性肝癌患者和1,353例慢性HBV携带者进行中国人白细胞抗原（HLA）基因分型，并分析其与HBV相关性肝癌的关系。条件分析用于识别与HBV相关HCC风险相关的独立信号（P错误发现率（FDR）<0.20）。对MHC区域内的总共14，930个变体进行了基因分型或插补。结果我们确定了两个变异，rs 114401688（P = 1.05 × 10−6，PFDR = 2.43 × 10−3）和rs 115126566（P = 9.04 × 10−5，PFDR = 1.77 × 10−1），它们与HBV相关HCC的风险独立相关。单核苷酸多态性（SNP）rs 114401688与先前报道的SNP rs 9275319连锁不平衡。在目前的研究中，我们发现它与肝癌的关联可以用HLA-DQB 1 *04和HLA-DRB 1 *04来解释。SNP rs 115126566是一种新的风险变异，可能通过增强子介导的机制调节HLA-DPA 1/DPB 1的转录。HLA-DQB 1基因纯合性分析显示，HLA-DQB 1基因纯合性与肝癌发病风险显著相关（P = 0.10），且在年龄≥50岁组中，其发病风险更高（P = 0.03）。讨论我们的研究结果进一步理解了慢性HBV携带者中HBV相关HCC易感性的遗传基础。
Introduction Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive. Methods With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed. Results We identified two variants, rs114401688 (P = 1.05 × 10−6, PFDR = 2.43 × 10−3) and rs115126566 (P = 9.04 × 10−5, PFDR = 1.77 × 10−1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03). Discussion Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.