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Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

ABSTRACT: 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.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.

SUBMITTER: Janse M

PROVIDER: S-EPMC3121050 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

Janse Marcel M Lamberts Laetitia E LE Franke Lude L Raychaudhuri Soumya S Ellinghaus Eva E Muri Boberg Kirsten K Melum Espen E Folseraas Trine T Schrumpf Erik E Bergquist Annika A Björnsson Einar E Fu Jingyuan J Jan Westra Harm H Groen Harry J M HJ Fehrmann Rudolf S N RS Smolonska Joanna J van den Berg Leonard H LH Ophoff Roel A RA Porte Robert J RJ Weismüller Tobias J TJ Wedemeyer Jochen J Schramm Christoph C Sterneck Martina M Günther Rainer R Braun Felix F Vermeire Severine S Henckaerts Liesbet L Wijmenga Cisca C Ponsioen Cyriel Y CY Schreiber Stefan S Karlsen Tom H TH Franke Andre A Weersma Rinse K RK

Hepatology (Baltimore, Md.) 20110502 6

<h4>Unlabelled</h4>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 initial ...[more]

PMID: 21425313

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Project description:ObjectivesThe clinical/colonoscopic features of ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC), the prognostic impact of UC, and the utility of UC screening in PSC patients are unknown. We characterized UC associated with PSC and assessed UC's impact on the prognosis of PSC and the importance of colonoscopic UC screening in PSC patients.MethodsWe retrospectively analyzed the cases of 77 patients treated for PSC at a single center (April 2000-July 2019). We reviewed the clinical/colonoscopic profiles of the concurrent UC patients and compared the clinical profiles, survival, and primary causes of death between the patients with/without UC (n = 35/n = 42). The details of all patients' colonoscopies were reviewed.ResultsThe concurrent UC group: 17 men, 18 women, diagnosed with PSC at the mean (SD) age of 36 (17) years; 21 patients (60%) had no UC symptoms. Colonoscopy revealed pancolitis in all patients, predominantly affecting the right-sided colon in 30 patients (86%). Lesions were scattered. Backwash ileitis (n = 13, 37%) and rectal sparing (n = 18, 51%) were observed. Most patients had mild UC; some had moderate or more severe UC (median Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 2; range, 1-5). Ludwig's stage determined by liver biopsy did not correlate with the Mayo endoscopic score for UC. The patients with UC were diagnosed with PSC at a significantly younger age than those without UC (mean (SD), 36 [17] years vs. 55 [19] years, p < 0.0001) and had a significantly higher 5-year survival rate (97.1% vs. 70.5%, p = 0.0028). UC was detected in 19 of 34 asymptomatic patients (56%) who underwent colonoscopy screening.ConclusionsOur cohort's clinical/colonoscopic features of UC associated with PSC are more moderate or severe UC than previous cases. The coexistence of UC might affect the prognosis of PSC. In this regard, colonoscopy in PSC patients is an important examination for determining prognosis. There is also asymptomatic UC in patients with PSC. In this regard, screening for colonoscopy in PSC patients is essential. When a diagnosis of PSC is made, immediate colonoscopy is a priority with UC complications in mind.

Dataset Information

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

Publications

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

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