title: CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.
abstract: CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
authors.affiliation: Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.forename: Habib
authors.initials: H
authors.lastname: Zouali
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cézard
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: Jacques
authors.initials: J
authors.lastname: Belaiche
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.forename: Curt
authors.initials: C
authors.lastname: Tysk
authors.forename: Colm
authors.initials: C
authors.lastname: O'Morain
authors.forename: Miquel
authors.initials: M
authors.lastname: Gassull
authors.forename: Vibeke
authors.initials: V
authors.lastname: Binder
authors.forename: Yigael
authors.initials: Y
authors.lastname: Finkel
authors.forename: Robert
authors.initials: R
authors.lastname: Modigliani
authors.forename: Corinne
authors.initials: C
authors.lastname: Gower-Rousseau
authors.forename: Jeanne
authors.initials: J
authors.lastname: Macry
authors.forename: Françoise
authors.initials: F
authors.lastname: Merlin
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jannot
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins