title: Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.
abstract: Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings.
authors.affiliation: Department of Clinical and Experimental Medicine; Translational Research Center for Gastrointestinal Disorders (TARGID); KU Leuven; Leuven, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Hoefkens
authors.forename: Kris
authors.initials: K
authors.lastname: Nys
authors.forename: Jestinah M
authors.initials: JM
authors.lastname: John
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Arijs
authors.forename: Jan
authors.initials: J
authors.lastname: Van der Goten
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
mesh_terms: D000328:Adult; D000483:Alleles; D000890:Anti-Infective Agents / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents
keywords: Crohn disease; ER stress; autophagy; genetic interaction; ulcerative colitis