Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis

Background: Patients with ulcerative colitis who are likely to have primary sclerosing cholangitis should be identified since PSC can influence UC clinical behavior and outcomes. Aim: To establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. Materials and Methods: We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate data sets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve (AUC). Results: Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P=1.57E-04), younger diagnosis age (<20 years; OR, 2.22; P=.02), and less smoking (OR, 0.42; P=.02) than those with UC. After LD pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (AUC, 88%). Conclusions: Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.