Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 4950 Nydalen, 0424, Oslo, Norway.
Clin Rev Allergy Immunol. 2015 Jun;48(2-3):154-64. doi: 10.1007/s12016-014-8417-z.
A role of genetics in primary sclerosing cholangitis (PSC) development is now firmly established. A total of 16 risk genes have been reported at highly robust ("genome-wide") significance levels, and ongoing efforts suggest that the list will ultimately be considerably longer. Importantly, this genetic risk pool so far accounts for less than 10 % of an estimated overall PSC susceptibility. The relative importance of genetic versus environmental factors (including gene-gene and gene-environment interactions) in remaining aspects of PSC pathogenesis is unknown, and other study designs than genome-wide association studies are needed to explore these aspects. For some of the loci, e.g. HLA and FUT2, distinct interacting environmental factors may exist, and working from the genetic associations may prove one valid path for determining the specific nature of environmental triggers. So far the biological implications for PSC risk genes are typically merely hypothesized based on previously published literature, and there is therefore a strong need for dedicated translational studies to determine their roles within the specific disease context of PSC. Apparently, most risk loci seem to involve in a subset of biological pathways for which genetic associations exist in a multitude of immune-mediated diseases, accounting for both inflammatory bowel disease as well as prototypical autoimmunity. In the present article, we will survey the current knowledge on PSC genetics with a particular emphasis on the pathophysiological insight potentially gained from genetic risk loci involving in this profound immunogenetic pleiotropy.
原发性硬化性胆管炎（PSC）的发病机制中遗传因素的作用现在已经得到了明确证实。目前已经报道了 16 个具有高度稳健性（“全基因组”）意义的风险基因，并且正在进行的研究表明，这一清单最终可能会更长。重要的是，到目前为止，这一遗传风险池仅占估计的 PSC 总易感性的不到 10%。遗传因素与环境因素（包括基因-基因和基因-环境相互作用）在 PSC 发病机制的其余方面的相对重要性尚不清楚，需要采用全基因组关联研究以外的其他研究设计来探讨这些方面。对于一些基因座，例如 HLA 和 FUT2，可能存在不同的相互作用的环境因素，并且从遗传关联入手可能是确定环境触发因素具体性质的有效途径之一。到目前为止，PSC 风险基因的生物学意义通常仅仅是基于先前发表的文献进行假设，因此非常需要专门的转化研究来确定它们在 PSC 这一特定疾病背景下的作用。显然，大多数风险基因座似乎都涉及一组生物学途径，这些途径在多种免疫介导的疾病中存在遗传关联，包括炎症性肠病和典型的自身免疫性疾病。在本文中，我们将重点介绍 PSC 遗传学的现有知识，特别强调涉及这种广泛免疫遗传多效性的遗传风险基因座可能获得的病理生理学见解。
