Zhang Min, Lyu Liang, Ge Liang, Wang Yizhou, Gu Dongqing
Department of Sleep and Psychology, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of College of Medical Informatics, Chongqing Medical University, Chongqing, China.
Front Immunol. 2025 Aug 29;16:1600364. doi: 10.3389/fimmu.2025.1600364. eCollection 2025.
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.
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.
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 (DQA10401, DQB10301, DQB10402, DQB10602, DRB108, DRB10803, DRB111, DRB11101, 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 (A3303, B4403, DPB10201, DQB10401, rs231725, rs231775, rs1544410, and rs9303277) with PBC at the genome-wide significance level ( < 5.0 × 10). 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 (< 6.43×10).
This study provides the most comprehensive synopsis to date of PBC's genetic architecture, highlighting robust HLA and non-HLA risk loci.
https:///www.crd.york.ac.uk/PROSPERO/view/CRD42021282146, identifier CRD42021282146.
尽管针对原发性胆汁性胆管炎（PBC）进行了广泛的基因研究，但与风险相关的变异的机制基础仍知之甚少。为了填补这一空白，我们对将基因变异与PBC易感性联系起来的累积证据进行了系统评估。
进行了全面搜索，以识别已发表的关于基因变异与PBC风险关联的研究。具体而言，对全基因组关联研究（GWAS）和候选基因关联研究进行了单独分析，以解决因研究设计差异而产生的潜在异质性。对候选基因关联研究进行荟萃分析，以计算合并比值比（OR）和95%置信区间（CI）。使用威尼斯标准和假阳性报告概率（FPRP）测试对显著关联进行进一步分级。进行功能注释、通路富集和全表型组分析，以阐明生物学相关性。
总体而言，我们纳入了105篇文章，涉及71,031例病例和140,499例对照。对33个基因中的70个变异进行了荟萃分析。其中，44个变异被确定与PBC风险显著相关，包括30个HLA变异和14个非HLA变异。另外，已发表的GWAS报告了115个显著变异。两种方法都鉴定出9个变异（DQA10401、DQB10301、DQB10402、DQB10602、DRB108、DRB10803、DRB111、DRB11101和rs7574865）。此外，候选基因关联研究的荟萃分析提供了强有力的证据，支持另外8个变异（A3303、B4403、DPB10201、DQB10401、rs231725、rs231775、rs1544410和rs9303277）在全基因组显著性水平（<5.0×10）与PBC相关。通路分析显示，映射基因在免疫细胞调节和免疫反应调节信号通路中显著富集。全表型组分析进一步表明，错义变异rs231775与甲状腺问题和黑色素瘤显著相关（<6.43×10）。
本研究提供了迄今为止关于PBC遗传结构最全面的概述，突出了强大的HLA和非HLA风险位点。
https:///www.crd.york.ac.uk/PROSPERO/view/CRD42021282146，标识符CRD42021282146。
