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Multicenter Study
, 53 (6), 1977-85

Three Ulcerative Colitis Susceptibility Loci Are Associated With Primary Sclerosing Cholangitis and Indicate a Role for IL2, REL, and CARD9

Multicenter Study

Three Ulcerative Colitis Susceptibility Loci Are Associated With Primary Sclerosing Cholangitis and Indicate a Role for IL2, REL, and CARD9

Marcel Janse et al. Hepatology.


Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates.

Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.

Conflict of interest statement

Authors’ disclosure

The authors have no financial, professional or personal conflicts of interest to declare.


Figure1. Gene Relationships Across Implicated Loci (GRAIL) pathway analysis
Links between genes at nine Primary Sclerosing Cholangitis associated loci. Specifically, all of the nine PSC-associated SNPs are in LD intervals containing, or within 50kb of at least one known gene. In total there are 100 genes implicated by proximity to these nine SNPs. Each observed PSC-association was scored with GRAIL, which takes all genes mapping within PSC-associated intervals and evaluates for each whether it is non-randomly linked to the other genes, via word-usage in PubMed abstracts. The lines between genes represent individually significant connections that contribute to the positive signal, with the thickness of the lines being inversely proportional to the probability that a literature-based connection would be seen by chance.

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