Genetic architecture of primary biliary cholangitis: strong evidence for HLA and non-HLA risk loci

作者：Min Zhang, Liang Lyu, Liang Ge, Yizhou Wang, Dongqing Gu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1600364 · 被引用次数：4 · 研究领域：Liver Diseases and Immunity、Cholangiocarcinoma and Gallbladder Cancer Studies、Pediatric Hepatobiliary Diseases and Treatments

Background Despite extensive genetic studies investigating primary biliary cholangitis (PBC), the mechanistic basis of risk-associated variants remains poorly understood. To address this gap, we performed a systematic evaluation of cumulative evidence linking genetic variants to PBC susceptibility. Methods A comprehensive search was conducted to identify published studies on the association between genetic variants and PBC risk. Specifically, separate analyses were conducted for genome-wide association studies (GWASs) and candidate-gene association studies to address potential heterogeneity arising from differences in study design. Meta-analyses were performed to calculate pooled odds ratio (OR) and 95% confidence interval (CI) for the candidate-gene association studies. Significant associations were further graded using Venice criteria and false-positive report probability (FPRP) tests. Functional annotation, pathway enrichment, and phenome-wide analyses were performed to elucidate biological relevance. Results Overall, we included 105 articles involving 71,031 cases and 140,499 controls. Meta-analyses were conducted for 70 variants across 33 genes. Among these, 44 variants were identified as significantly associated with PBC risk, comprising 30 HLA variants and 14 non-HLA variants. Separately, published GWAS have reported 115 significant variants. Nine variants (DQA1*0401, DQB1*0301, DQB1*0402, DQB1*0602, DRB1*08, DRB1*0803, DRB1*11, DRB1*1101, and rs7574865) were identifie...