Introduction Recent genetic studies in Primary sclerosing cholangitis (PSC), a chronic bile duct disease, have shown suggestive association at IL-2/21 (4q27) and IL2RA (10p15). IL-2 and IL2RA are key regulators of immune tolerance. To further refine association at 4q27 and 10p15, a fine mapping study was undertaken in 1030 British PSC cases and 5162 healthy controls.
Methods For SNP selection, 80 Kbp and 564 Kbp regions were selected on 10p15 and 4q27, respectively, and SNP data from HapMap Data Rel 24/phase II was used to identify tag SNPs with Haploview v4.2. 62 tag SNPs were genotyped on a Sequenom platform. Control genotype data were available for 62 SNPs, previously genotyped in the Wellcome Trust Case Control Consortium 2 (WTCCC 2). 59 SNPs (28 at 4q27 and 31 at 10p15) passed quality control and were analysed using logistic regression in PLINK v1.07. For selected SNPs, previously published summary statistics1 were used to perform a meta-analysis.
Results Significant association (p<8.5×10−4) corrected for multiple testing (Bonferroni method) was observed for one SNP at 4q27 and three SNPs at 10p15 (Abstract PTU-070 table 1). In addition, nominal significance (p<0.05) was seen for 9/27 SNPs at 4q27 and 10/28 SNPs at 10p15. Genome-wide significance (p<5×10−8) was observed for rs4147359 (10p15) in the combined analysis.
Conclusion This study confirms the IL2RA and IL-2/IL-21 locus association in PSC suggesting a role of adaptive immune responses. Genetic variants at these loci are associated with autoimmune diseases. Association of PSC with variants at these loci could imply not only a shared genetic risk with other diseases but also identify the immunological pathways favouring disease development. Functional studies are now required to identify the causative gene or genes to facilitate rapid translation to the discovery of novel therapeutics.
Competing interests None declared.
Reference 1. Melum E, et al. Nat Genet 2011;43:17–19.