From the AGA Journals

Four genes linked to phenotypic traits of Crohn’s disease




Four gene loci in patients with Crohn’s disease were significantly linked with phenotypic traits such as erythema nodosum or having a complicated or mild course of disease, researchers reported in the April issue of Gastroenterology (doi:10.1053/j.gastro.2014.12.030).

The work is the first genome-wide study to link specific genetic loci with clinically relevant traits in patients with Crohn’s disease (CD), said Dr. Arnald Alonso at the Vall d’Hebron Research Institute and the University of Catalonia in Barcelona and his associates. “Importantly, these new loci have not been previously described as risk factors for CD,” the researchers said. “Our results therefore demonstrate the existence of a genetic component for disease heterogeneity that is independent of the genetic variation associated with the susceptibility to Crohn’s disease.”

Crohn’s disease varies greatly in terms of severity, location of pathology, complications, and other factors. Genome-wide association studies have linked 140 genetic “risk loci” with susceptibility to CD, but past work has only found one gene locus (NOD2) that is definitively linked a single clinical trait of CD (ileal pathology), the investigators noted. For their genome-wide association study, they genotyped 576,818 single nucleotide polymorphisms in a discovery cohort of 1,090 CD patients of European ancestry who presented at university hospitals in Spain between 2007 and 2010, as well as 1,493 healthy controls. They examined associations between these genetic markers and 17 characteristics (or phenotypes) of CD related to disease location, disease behavior and course, age at onset, and extra-intestinal manifestations of CD. Next, the investigators studied a separate “replication” cohort of 1,296 CD patients in order to assess the 57 markers that had been most strongly associated (P < .0002) with CD phenotypes among the discovery cohort (Gastroenterology,

These combined analyses showed that clinical phenotypes in CD were most significantly linked with four markers, including MAGI1, CLCA2, 2q24.1, and LY75, reported the investigators. The MAGI1 gene was found to predict complicated structuring disease course and stricturing behavior in CD, although it did not appear to speed its onset, they said. The gene encodes proteins that have been found to play an important role in the tight junctions between epithelial cells, and consequently in intestinal barrier function, they noted, adding that disruption of that mucosal integrity contributes to the pathogenesis of ulcerative colitis and CD. “Importantly, an increased intestinal permeability has been described in patients with active CD as well as in their first-degree relatives,” they added. “This evidence strongly suggests that increased intestinal permeability is not only a consequence of intestinal inflammation occurring in CD patients, but it is rather a risk factor for CD.”

The other three loci that were significantly associated with CD traits predicted ileal involvement (CLCA2), erythema nodosum (LY75), and having a mild disease course (2q24.1), the researchers reported. Taken together, the findings “indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease,” concluded Dr. Alonso and his associates. “Further functional studies of these new loci will provide a better understanding of the biological mechanisms that are involved in the development of these relevant clinical phenotypes.”

The Spanish Ministry of Economy and Competitiveness funded the study. The investigators reported having no relevant financial disclosures.

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