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

Abstract

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, OR_{A vs G} = 1.28, 95% CI (1.16–1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10^-4, OR_{A vs G} = 1.20, 95% CI (1.09–1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10^-4, OR_{A 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.

Key Words::

• fine mapping study
• genetic association
• IL-2/IL-21
• IL2RA
• primary sclerosing cholangitis

Acknowledgements

The authors wish to thank all PSC cases and healthy controls for their participation. We acknowledge the Wellcome Trust Case Control Consortium (WTCCC) for providing the healthy control genotype data. We greatly acknowledge all the principal investigators of the UK-PSC consortium and the National Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN) led research nurse support received for recruiting the patients enrolled in this study. This study was supported by the UK-based PSC support charity (Registered charity number 1115615) and the Norwegian PSC research center. GFM is a Clinical Research Training Fellow of the Medical Research Council (G0800460). He is also supported by a Raymond and Beverly Sackler Studentship. Study concept and design: B.S., T.H.K., E.M. Case ascertainment and phenotyping: B.S., A.W.M., M.B., The UK-PSC Consortium (see Supplementary material for details), R.W.C., S.M.R. Genotyping of cases: E.E., A.F. Control genotype data ascertainment: G.F.M., R.N.S., H.J.C. Analysis and interpretation of data: B.S., G.F.M., H.J.C., E.M. Manuscript preparation: B.S., R.N.S., E.M. Revised the manuscript: S.M.R., H.J.C., E.E., T.H.K., G.J.A. All authors approved of the final version.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.