Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis

Document Type



School of Nursing and Midwifery, East Africa


Background and aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC.

Methods: We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls.

Results: The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10-6, ORA vs G = 1.28, 95% CI (1.16–1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10-4, ORA vs G = 1.20, 95% CI (1.09–1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10-4, ORA vs T = 1.21, 95% CI (1.09–1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P combined = 3.8 × 10-12) and rs4147359 (10p15 (IL2RA), P combined = 1.5 × 10-8).

Conclusion: We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.


Scandinavian Journal of Gastroenterology