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.

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…Lesage et al 12 suggested that patients carrying two variant copies of the CARD15/NOD2 gene are at increased risk of ileal involvement, early age at diagnosis and fibrostenotic behaviour of disease. Ahmad et al, 11 Cuthbert et al, 10 and others 9,19,22,25 have also suggested that carriage of allelic variants is associated with ileal involvement in CD. However, as further data emerge, the primary genotype-phenotype relationship remains controversial and most limited by the quality of phenotypic data.…”

“…The contribution of the gene has been studied in many diverse populations, [7][8][9][10][11] with positive associations in up to 50% of CD patients. 12 However, data from Japanese, Korean and African-American individuals have not shown an association, [13][14][15] and there are now clear differences between Ashkenazi Jewish and nonJewish populations.…”

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

“…In the IBD-2 collection, self-declared healthy control subjects were matched to cases on the basis of ethnicity. 53 Collection IBD-3 is described below. Collection IBD-4 consists of Belgian subjects of European ancestry collected at the Erasme Hospital, Brussels.…”

“…53 All genotypes on collections IBD-1 to -5 were generated by the genotyping center of the Whitehead Institute Center for Genome Research (now called the Broad Institute). We used data only from those SNPs that showed 490% genotyping success, did not deviate from Hardy-Weinberg equilibrium (P40.001) in the control subjects, and had one or fewer Mendelian error in each trio collection (IBD-1 to -5).…”

NOD2 gene mutations in ulcerative colitis: useless or misunderstood?

“…Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) also contribute to clinical phenotype and natural history, being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. In CD, NOD2 gene mutations have repeatedly been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49]. Surprisingly, there are no studies focusing on potential genotype-phenotype associations between NOD2 mutations and UC, perhaps because it is not commonly considered a susceptibility gene for UC [5,10,50].…”