Effect of inflammatory bowel disease classification changes on NOD2 genotype-phenotype associations in a population-based cohort.

BACKGROUND: NOD2 mutations are associated with Crohn's disease (CD) in Caucasian clinic-based cohorts. Data from population-based cohorts are limited. Clinic-based studies may overestimate this association. Genotype-phenotype relationships are yet to be assessed using the Montreal classification. We hypothesized that the NOD2-CD association would be weaker in a population-based cohort, and that the Montreal classification would strengthen genotype-phenotype associations. METHODS: A population-based case-control study was performed including 91% of all people in Canterbury, New Zealand, with inflammatory bowel disease (IBD); NOD2 genotyping was performed and patients were phenotyped according to the Vienna and Montreal classification systems. RESULTS: The NOD2 genotype was available on 684 CD, 643 ulcerative colitis (UC), 36 indeterminate colitis/IBDU (IBD unclassified) patients, and 201 controls. Control frequencies for the 702W, 908R, and 1007fs alleles were 0.030, 0.012, and 0.010, respectively, compared with 0.074, 0.027, and 0.040 for CD. The 702W (P = 0.001) and 1007fs (P = 0.002) alleles were significantly associated with CD. Younger age of diagnosis (<17 years) was associated with 1 (odds ratio (OR) 1.9 [95% confidence intervals 0.98-3.6]) or 2 (OR 6.5 [2.3-18.6]) NOD2 mutations compared with diagnosis >40 years. Ileal disease was most strongly associated with NOD2 mutations (1 mutation OR 3.9 [2.4-6.3], 2 mutations OR 6.7 [2.4-18.5]). Penetrating disease was associated with NOD2 mutations using the Montreal but not the Vienna classification. CONCLUSIONS: The association between NOD2 mutations and CD was found to be weaker in our population-based cohort than in previous studies that used referral-based cohorts. Application of the Montreal classification led to a strengthening of the NOD2 genotype-phenotype association.

Caspase recruitment domain-containing protein 15 mutations in patients with colorectal cancer.

The caspase recruitment domain-containing protein 15 (CARD15) plays a crucial role in mediating the innate immune response. Mutations within this protein have been shown to be independent risk factors for the development of Crohn's disease in Caucasians. As Crohn's disease patients are at increased risk of developing sporadic colorectal cancer, it is conceivable that genetic variability within CARD15 may also play a role in determining susceptibility to this gastrointestinal malignancy in individuals without Crohn's disease. This hypothesis is supported by the findings of two case-control studies that found the frequencies of CARD15 mutations were significantly elevated in Polish and Greek colorectal cancer patients. Given the results of these previous studies, we examined whether the high incidence of sporadic colorectal cancer observed in New Zealand Caucasians was due to mutations within CARD15. To answer this question, we genotyped 133 colorectal cancer patients and 201 Caucasian controls for R702W, G908R, 1007fs, and P268S. Chi(2) Testing found that the combined frequency of R702W, G908R, and 1007fs was significantly elevated in colorectal cancer patients compared with controls (P = 0.001; odds ratio, 2.8; 95% confidence interval, 1.5-5.4), but no association was detected between tumor behavior or age of disease onset and CARD15 mutations in our colorectal cancer cohort. This study is the first to explore the link between CARD15 mutations and colorectal cancer in New Zealand Caucasians. Our results strongly suggest that CARD15 influences susceptibility to colorectal cancer, but we have found no evidence to indicate that CARD15 mutations predict the clinicopathologic characteristics of this disease.