Genetic epidemiology of primary sclerosing cholangitis

Abstract

The aetiology of primary sclerosing cholangitis (PSC) is not known. A more than 80-fold increased risk of PSC among first-degree relatives emphasizes the importance of genetic factors. Genetic associations within the human leukocyte antigen (HLA) complex on chromosome 6p21 were detected in PSC 25 years ago. Subsequent studies have substantiated beyond doubt that one or more genetic variants located within this genetic region are important. The true identities of these variants, however, remain to be identified. Several candidate genes at other chromosomal loci have also been investigated. However, according to strict criteria for what may be denominated a susceptibility gene in complex diseases, no such gene exists for PSC today. This review summarises present knowledge on the genetic susceptibility to PSC, as well as genetic associations with disease progression and clinical subsets of particular interest (inflammatory bowel disease and cholangiocarcinoma).

Figure 1

Primary sclerosing cholangitis (PSC) is a patchwork of different phenotypes in addition to the bile duct involvement. Most important are inflammatory bowel disease (IBD), malignancy and other autoimmune diseases. PSC is distinct from secondary sclerosing cholangitis (SSC).

Figure 2

Statistical power (α = 0.05) for different odds ratios and allele frequencies in a study of 365 patients and 365 controls, i.e., the number of alleles in each group is 2 n = 730.

Figure 3

Schematic outline of the HLA complex on chromosome 6. Distances are arbitrary. By convention, the extended HLA complex stretches from the centromeric border of the HLA class II loci (HLA-DP) to the telomeric limit of the histone gene cluster more than 4 million bp from HLA-A[43,120]. Centromeric to the HLA-DQ loci, a region with intense recombination can be found ("recombination hot-spot")[132].