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Published on: September 22, 2019
CARD15 genotype-phenotype relationships in a small inflammatory bowel disease population with severe disease
Nigel P S Crawford1, Daniel W Colliver, M Robert Eichenberger
1Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Insights
Three CARD15 gene mutations are linked to increased susceptibility to Crohn's disease (CD), a type of inflammatory bowel disease (IBD). These mutations are associated with specific CD subphenotypes, including early-onset disease and complications.
Area of Science:
- Genetics
- Gastroenterology
- Immunology
Background:
- Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC).
- Specific mutations in the CARD15 gene (R702W, G908R, 1007fs) have been previously linked to CD susceptibility.
- These mutations are associated with ileal or ileocolonic CD, particularly with fibrostenosing characteristics.
Purpose of the Study:
- To replicate previously identified associations between CARD15 mutations and CD in a well-phenotyped cohort.
- To investigate the association of CARD15 mutations with specific CD subphenotypes.
- To analyze CARD15 mutant allele and haplotype data using case-control and family-based approaches.
Main Methods:
- Association study involving 477 IBD patients (248 CD, 172 UC, 57 IC) and 104 controls.
- Utilized case-control and family-based (pedigree disequilibrium testing) analyses for CARD15 mutations.
- Phenotypic subtyping of CD patients to identify associations with specific disease characteristics.
Main Results:
- The R702W allele showed a significant association with CD in case-control analysis (q=0.036).
- The 1007fs mutation was associated with CD in pedigree disequilibrium testing (P=.020).
- All three CARD15 mutations were linked to increased susceptibility for various CD subphenotypes, including early-onset disease, family history of IBD, extraintestinal manifestations, and ileal/ileocolonic disease.
Conclusions:
- Replication of CARD15 mutation associations with CD susceptibility in a defined cohort.
- Confirmation that CARD15 mutations are associated with terminal ileal/ileocolonic and fibrostenosing CD.
- Evidence suggests CARD15 mutations may predispose to a more generalized form of CD, influencing early onset and extraintestinal disease.
Abstract:
Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.
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