Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation(1-3). We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip(4). We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

“…In addition, an intronic SNP in SIK2 confers susceptibility to primary sclerosing cholangitis, a degenerative liver disease that shares significant comorbidity with IBD (33). These human genetic data potentially implicate EP4-SIK2-CRTC3-CREB signaling as a contributor to IBD (patho)physiology via regulation of gut IL-10 levels, and make it an intriguing target for therapeutic manipulation.…”

Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity

“…In order to investigate the shared genetics of autoimmune and immune-related diseases, we selected eight different AID for which dense-mapped Immunochip data were available (per 1 June 2013): autoimmune thyroid disease [43], celiac disease (CeD) [44], inflammatory bowel disease (IBD) [45], juvenile idiopathic arthritis (JIA) [46], primary biliary cirrhosis (PBC) [47], psoriasis (PS) [48], primary sclerosing cholangitis (PsCh) [49] and rheumatoid arthritis (RA) [50]. We sub-divided IBD loci into Crohn's disease (CD)-specific loci, ulcerative colitis (UC)-specific loci, and CD-UC shared loci (IBD shared) to reveal phenotypespecific features.…”

Biomarkers for disease progression of primary sclerosing cholangitis

“…[79][80][81][82] It is still unknown whether individual differences in PSC sub-phenotypes are driven by genetic background. The PSC Immunochip sub-phenotyping project, a study initiated by the International PSC study group (IPSCSG) is currently investigating, these possible associations between PSC risk loci and PSC sub-phenotype.…”