Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan.
Genes (Basel). 2023 Feb 3;14(2):405. doi: 10.3390/genes14020405.
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
原发性胆汁性胆管炎（PBC）是一种慢性、进行性胆汁淤积性肝病，其特征是小的肝内胆管被自身免疫反应破坏。在自身免疫性疾病中，这些疾病是多基因复杂特征，由遗传和环境因素的共同贡献引起，PBC 在疾病发展中表现出最强的遗传遗传性。截至 2022 年 12 月，全基因组关联研究（GWAS）和相关的荟萃分析在包括欧洲和东亚血统在内的不同人群中确定了大约 70 个 PBC 易感性基因座。然而，这些易感性基因座通过何种分子机制影响 PBC 的发病机制尚不完全清楚。本研究概述了 PBC 的遗传因素以及 GWAS 后确定疾病易感性基因座中主要功能变异和效应基因的方法。还讨论了这些遗传因素在 PBC 发展中的可能机制，重点关注通过计算机基因集分析鉴定的四个主要疾病途径，即（1）人类白细胞抗原的抗原呈递，（2）白细胞介素 12 相关途径，（3）细胞对肿瘤坏死因子的反应，以及（4）B 细胞激活、成熟和分化途径。
