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CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure
Severine Vermeire1, Gary Wild, Kerry Kocher
1Department of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Canada.
Insights
Genetic variants in the caspase recruitment domain gene (CARD15) are strongly associated with Crohn disease (CD) susceptibility in a Quebec population. These CARD15 mutations are linked to ileal disease and can be detected using common single-nucleotide polymorphisms.
Area of Science:
- Genetics
- Gastroenterology
- Molecular Biology
Background:
- The caspase recruitment domain gene (CARD15) is linked to the IBD1 locus, conferring susceptibility to Crohn disease (CD).
- Three specific CARD15 sequence variants (Arg702Trp, Gly908Arg, Leu1007fsinsC) have been previously associated with CD.
- Understanding the prevalence and phenotypic correlations of these variants in diverse populations is crucial.
Purpose of the Study:
- To determine the prevalence of CARD15 sequence variants in an independent Canadian population from Quebec.
- To analyze genotype-phenotype correlations, specifically the association of CARD15 variants with disease location.
- To investigate the haplotype structure around CARD15 using single-nucleotide polymorphisms (SNPs).
Main Methods:
- A cohort of 231 CD patients and 71 healthy controls from Quebec was recruited.
- Clinical records were reviewed for detailed phenotypic information.
- DNA samples were genotyped for three specific CARD15 variants (Arg702Trp, Gly908Arg, Leu1007fsinsC) and 45 surrounding SNPs.
Main Results:
- 45.0% of CD patients carried at least one CARD15 variant, versus 9.0% of controls (P<10-7).
- CARD15 variants were equally frequent in familial and sporadic CD cases.
- A significant association was found between CARD15 variants and ileal disease involvement (P<.001).
- Haplotype analysis revealed the history of causal mutations and demonstrated that CARD15 involvement is detectable using publicly available SNPs.
Conclusions:
- CARD15 variants are prevalent in the Quebec population and strongly associated with Crohn disease.
- These variants are specifically linked to ileal disease, providing a valuable genotype-phenotype correlation.
- The study highlights the utility of common SNPs in detecting CARD15's role in CD pathogenesis.
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.