“
“Melum E, Franke A, Schramm C, Weismüller TJ, Gotthardt DN, Offner FA, et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011;43: 17-19. (Reprinted with permission.) Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel mTOR inhibitor disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025

PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). The etiopathogenesis of primary sclerosing cholangitis (PSC) remains unknown, although it is now accepted that genetic factors play a major role in the development of the disease.1 First-degree relatives have an 80-fold–increased risk of developing PSC.2 Moreover, studies that were first carried out 30 years ago established that there are close associations with the human leukocyte antigen (HLA) complex on chromosome 6p21.3 Surprisingly, the exact gene or genes responsible for the association in this highly polymorphic region have not been identified.1, 2 The heritability of PSC has an estimated

relative sibling risk of approximately 10, which is in the range of other HLA-associated conditions.2 PSC is likely to be a complex disease in which different environmental factors interact with multiple genetic factors and learn more contribute to both the pathogenesis and progression of this chronic cholestatic biliary disease. PSC is characterized by a close association with inflammatory bowel disease and particularly ulcerative medchemexpress colitis, which coexists in approximately three-quarters of Northern European patients with PSC.3 In addition, approximately 5% to 10% of patients with total ulcerative colitis will have or will develop PSC during the course of their illness. Intriguingly, the clinical phenotype of ulcerative colitis associated with PSC (inflammatory bowel

disease with PSC) exhibits significant differences with the ulcerative colitis phenotype without PSC,4 and this raises the possibility of significant genotypic differences between the patient groups. A recent meta-analysis of six genome-wide association study (GWAS) data sets for ulcerative colitis compared 6687 ulcerative colitis patients with 19,718 controls.5 The report identified 29 additional risk loci not previously identified for ulcerative colitis and thereby increased the number of ulcerative colitis– associated loci to 47. The authors documented that the number of confirmed risk loci in inflammatory bowel disease is 99; this number includes at least 28 association signals shared by ulcerative colitis and Crohn’s disease. In contrast, GWASs of liver disease in general and PSC in particular are in their infancy.