Deciphering the Genetic Predisposition to Primary Sclerosing Cholangitis

ABSTRACT

Genetic variants within the major histocompatibility complex (MHC) on chromosome 6 have been shown to confer risk for primary sclerosing cholangitis (PSC) ~30 years ago. However, robust genetic associations outside this genetic region have been difficult to establish. By genome-wide association analysis, a surprising large overlap of genetic risk loci outside of the MHC with prototypical autoimmune diseases has been recognized. In this article, we review the present knowledge of susceptibility loci in PSC, by assessing the robustness of the findings and speculating on potential mechanistic roles of predicted risk genes in PSC pathogenesis. We suggest a model where the primary insult is likely to resemble the tissue injury in most autoimmune conditions. Functional insight into risk pathways could offer novel therapeutic opportunities, and we speculate on specific opportunities that may arise based on current knowledge.

KEYWORDS

Primary sclerosing cholangitis - genetic predisposition - comorbidities - T lymphocytes - major histocompatibility complex

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