7 These HLA associations appear to be specific to PSC. For PSC, just as for the majority of HLA-associated

diseases, significant associations have been demonstrated outside the HLA complex with a gene present on chromosome 13q31. However, this gene is not specific to PSC because significant associations at this locus have been found for ulcerative colitis and multiple sclerosis. This suggests that the gene may be involved in the pathogenesis of inflammation rather check details than specific disease susceptibility. Further significant associations that were also previously established as ulcerative colitis susceptibility loci were detected on chromosomes 2q35 and 3p21.7 The authors suggested G-protein–coupled bile acid receptor 1 and macrophage stimulating 1 (MST1), respectively, as the likely genes involved in the disease process. In the latest study,8 the same group repeated and extended the GWAS by increasing the size of the Scandinavian and German study population and the replication cohort to 715 and 1025 PSC patients, respectively, although the numbers of patients included in the study are still relatively

small in comparison with the much larger numbers included in GWASs of inflammatory bowel disease. In agreement with the original study, the strongest associations were detected in the HLA complex. An analysis revealed a complex association signal in the class II region and confirmed the strong association with the HLA-B*08 locus in the class I region. This suggests multiple causative 5-Fluoracil loci within the region. Clear differences were found in the HLA complex in comparison with ulcerative colitis (for which the association signal is less extensive), and associated single-nucleotide polymorphisms (SNPs) were observed

near the HLA class II region. This is a potentially important observation that requires further the study in the search for the elusive PSC susceptibility gene or genes in this region. Outside the HLA complex, the findings of the first study were confirmed and extended. Multiple SNPs in strong linkage equilibrium at chromosome 3p21 were associated at a genome-wide significance level.8 Further analysis using the replication cohort demonstrated the most prominent association at MST1. The amino acid change at this locus, which is now associated with PSC and was previously demonstrated in patients with ulcerative colitis and Crohn’s disease,9 has been proposed to affect the MST1 receptor interaction. MST1 is known to encode macrophage stimulating protein, which regulates innate immune responses to bacterial ligands. The variant (rs3197999, R689C) identified in this study and previously in patients with inflammatory bowel disease9 has been predicted to interfere with the binding of macrophage stimulating protein to its receptor.