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

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 identified by both approaches. Additionally, meta-analyses of candidate-gene association studies provided strong evidence supporting the association of eight further variants (A*3303, B*4403, DPB1*0201, DQB1*0401, rs231725, rs231775, rs1544410, and rs9303277) with PBC at the genome-wide significance level ( P < 5.0 × 10 -8 ). Pathway analysis revealed significant enrichment of the mapped genes in immune cell regulation and immune response-regulating signaling pathways. Phenome-wide analyses further indicated that the missense variant rs231775 was significantly associated with thyroid problems and melanoma ( P < 6.43×10 -5 ). Conclusion This study provides the most comprehensive synopsis to date of PBC’s genetic architecture, highlighting robust HLA and non-HLA risk loci. Systematic review registration https:///www.crd.york.ac.uk/PROSPERO/view/CRD42021282146 , identifier CRD42021282146.