Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Postbox 4950Nydalen, 0424 Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postbox 1171 Blindern, 0318 Oslo, Norway.
Nat Rev Gastroenterol Hepatol. 2017 May;14(5):279-295. doi: 10.1038/nrgastro.2016.154. Epub 2017 Mar 15.
Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.
原发性硬化性胆管炎 (PSC) 是一种慢性疾病，可导致肝内和肝外胆管纤维化瘢痕形成，通过胆汁淤积性肝硬化、并发炎症性肠病和胆管癌的高风险导致相当大的发病率和死亡率。人们一直期望遗传研究能够确定 PSC 发病机制中的关键因素，以支持有效的医学治疗方法的发展。通过全基因组关联研究，已经确定了大量疾病易感性基因。PSC 的整体遗传结构与自身免疫性疾病和炎症性肠病具有共同特征。强烈的人类白细胞抗原基因关联，以及几个在 T 细胞功能中起关键作用的易感性基因，支持适应性免疫反应在疾病发病机制中的参与，并将 PSC 定位为自身免疫性疾病。在这篇综述中，我们调查了导致这些基因发现的发展情况。我们还详细阐述了在 PSC 中既定疾病模型背景下对个别基因发现的相关解释，并提出了相关的转化研究工作，以寻求新的见解。
