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. [ABSTRACT FROM AUTHOR]