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CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis
L E Oostenbrug1, I M Nolte, E Oosterom
1Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. l.e.oostenbrug@inter.nl.net
Insights
Caspase-Activation Recruitment Domain containing protein 15 (CARD15) gene variants are strongly associated with Crohn's disease, not ulcerative colitis. These variants correlate with small bowel involvement and a complicated disease course in Crohn's disease patients.
Area of Science:
- Genetics
- Gastroenterology
- Molecular Biology
Background:
- Three major polymorphisms in the Caspase-Activation Recruitment Domain containing protein 15 (CARD15) gene are linked to Crohn's disease.
- Existing genotype-phenotype studies present conflicting data regarding disease localization and behavior.
- The relationship between CARD15 and inflammatory bowel disease (IBD) phenotypes requires further investigation in large cohorts.
Purpose of the Study:
- To investigate the association of CARD15 gene variants with inflammatory bowel disease (IBD) and Crohn's disease (CD) phenotypic characteristics in a large Dutch cohort.
- To perform a pooled analysis of IBD patients and CD phenotypic characteristics from existing association studies.
- To clarify the conflicting data on CARD15's role in CD localization and behavior.
Main Methods:
- Genotyping of 781 cases and 315 controls for CARD15 variants (R702W, G908R, 1007fsinsC) and nearby microsatellite markers.
- Inclusion of data from 7201 IBD patients and 3720 controls across 20 studies for pooled analysis.
- Phenotype analysis focusing on disease characteristics, localization, and disease course.
Main Results:
- Significant association found between CARD15 variants (R702W, 1007fsinsC) and Crohn's disease, but not ulcerative colitis.
- Pooled analysis confirmed strong association of all three common CARD15 variants with Crohn's disease (p<0.00001; ORs 3.0-14.7).
- Phenotype analysis revealed association with small bowel involvement, stricturing, and penetrating disease characteristics.
Conclusions:
- CARD15 gene is definitively associated with Crohn's disease, with no association found for ulcerative colitis.
- All three common CARD15 variants are linked to small bowel involvement in Crohn's disease.
- The G908R and 1007fsinsC alleles are specifically associated with a complicated disease course in Crohn's disease.
Background:
Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies.
Methods:
We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included.
Results:
Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease.
Conclusion:
Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.
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