Genetic variants of UDP‐Glucuronosyltransferase 1A genes are associated with disease presentation and outcome in Primary Sclerosing Cholangitis

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease without a curative medical therapy. The human UDP-glucuronosyltransferases 1A play a major role in the detoxification and elimination of bilirubin, bile acids and xenobiotics. Whether genetic UGT1A variants determine course and outcome of PSC has not yet been described. METHODS: A large cohort of German PSC patients with a long-term-follow-up was genotyped for UGT1A variants including UGT1A1*28, UGT1A3-66 T>C and UGT1A7 p.N129K/p.R131K using TaqMan 5'-nuclease assays. Results were correlated with clinical characteristics and transplant-free survival. RESULTS: About 331 patients with PSC were included in the study (69.9% male, mean age at diagnosis 32.6 years). Median transplant-free survival was 14.9 years. Patients with wild-type alleles of all three UGT1A genes had a longer transplant-free survival (17.2 vs. 14.4 years, P = .048) than patients carrying a homozygous or heterozygous SNP variant in at least one of the UGT1A1, UGT1A3 or UGT1A7 genes. Additionally, we found that patients carrying wild-type alleles of all three UGT1A genes had lower serum bilirubin (25 vs. 38 µmol/L, P = .02) and serum cholesterol (195 vs. 223 mg/dL), P = .035) at first presentation. Furthermore, inflammatory bowel disease was found to be associated with wild-type UGT1A alleles (82.2% vs. 68.4%, P = .046). CONCLUSIONS: This large cohort shows an association with single nucleotide polymorphisms of the UGT1A1, UGT1A3 and UGT1A7 genes and outcome in PSC. Thus, UGT1A variants may represent a tool for the prognostic stratification of PSC patients and establish a link between disease progression and the regulation of detoxification by glucuronidation in PSC.