title: CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.
abstract: The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.
authors.affiliation: Department of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Canada.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Gary
authors.initials: G
authors.lastname: Wild
authors.forename: Kerry
authors.initials: K
authors.lastname: Kocher
authors.forename: Josee
authors.initials: J
authors.lastname: Cousineau
authors.forename: Line
authors.initials: L
authors.lastname: Dufresne
authors.forename: Alain
authors.initials: A
authors.lastname: Bitton
authors.forename: Diane
authors.initials: D
authors.lastname: Langelier
authors.forename: Pierre
authors.initials: P
authors.lastname: Pare
authors.forename: Gilles
authors.initials: G
authors.lastname: Lapointe
authors.forename: Albert
authors.initials: A
authors.lastname: Cohen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011792:Quebec
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D004247:DNA