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CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
Suzanne Lesage1, Habib Zouali, Jean-Pierre Cézard
1Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France.
Insights
Mutations in the CARD15 gene are linked to Crohn disease (CD) susceptibility. Specific CARD15 variants increase CD risk, with double mutations correlating to earlier onset and specific disease phenotypes, aiding genetic counseling.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- CARD15/NOD2 protein plays a role in monocyte bacterial recognition.
- Previous studies identified CARD15 mutations in Crohn disease (CD) patients.
- CD is a chronic inflammatory condition affecting the digestive tract.
Purpose of the Study:
- To analyze CARD15 gene mutations in a large cohort of Crohn disease patients.
- To identify specific CARD15 variants associated with CD susceptibility.
- To investigate the correlation between CARD15 mutations and disease phenotype.
Main Methods:
- Mutational analysis of the CARD15 gene in 453 CD patients, 159 ulcerative colitis (UC) patients, and 103 healthy controls.
- Sequencing variations were identified and allele frequencies were calculated.
- Association analysis was performed to link specific mutations to CD susceptibility and clinical characteristics.
Main Results:
- Three CARD15 variants (R702W, G908R, 1007fs) were independently associated with CD susceptibility.
- 50% of CD patients carried at least one disease-causing mutation (DCM), with 17% having a double mutation.
- Double CARD15 mutations were linked to younger age at onset, more frequent stricturing disease, and less colonic involvement.
Conclusions:
- Specific CARD15 mutations are confirmed risk factors for Crohn disease.
- A gene-dosage effect was observed, with double mutations influencing disease presentation.
- These findings support the development of DNA-based susceptibility tests and genetic counseling for inflammatory bowel disease.
Abstract:
CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.