Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease

Abstract

Chronic inflammatory bowel diseases (IBDs), specifically Crohn's disease (CD) and ulcerative colitis (UC), have increased significantly in western countries and Japan over the last decade, but very little is known about their pathogenesis. A candidate-gene approach recently identified NOD2/CARD15 as one susceptibility gene from the IBD1 locus on chromosome 16. Alterations in this gene were found in many Caucasian patients with CD; in particular, two nonsynonymous substitutions (R702W and G908R) and a frameshift mutation (1007fs) were shown to be independent risk factors for CD. We investigated DNA from 483 Japanese CD patients to detect those three mutations in NOD2/CARD15 by appropriate genotyping techniques, but found only an R702Q substitution in a single patient. Direct sequencing of DNA from 96 of our patients in the regions containing the three reported major mutations detected no sequence alterations of consequence. Our findings indicate that the NOD2/CARD15 gene is not a major contributor to CD susceptibility in the Japanese population.

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…Importantly, the Nod2 discovery provides specific support for the long-held hypothesis that CD results from a genetically dysregulated host immune response to luminal bacteria. These Nod2 mutations have not been observed in Japanese, Chinese and Koreans with IBD [49][50][51] , and they are rare in African-American IBD [52] .…”

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…The contribution of the gene has been studied in many diverse populations, [7][8][9][10][11] with positive associations in up to 50% of CD patients. 12 However, data from Japanese, Korean and African-American individuals have not shown an association, [13][14][15] and there are now clear differences between Ashkenazi Jewish and nonJewish populations. 16,17 Most recent data from Ireland and Northern Europe report relatively low allelic frequencies in healthy controls and CD patients (Table 1) and raise the possibility of heterogeneity within European populations of distinct ancestry.…”

No evidence for association of NOD2 R702W and G908R with colorectal cancer

“…6 In the Asian cohorts studied, NOD2 variants are rare and do not contribute to Crohn's disease, suggesting ethnic heterogeneity in disease predisposition. [7][8][9] In Europe, the disease susceptibility caused by the R702W, G908R and 3020insC variants appears less prominent in Finland, Sweden, Iceland, Scotland and Ireland, than in other populations. 1,3,4,10,11 For instance, in Scotland and Ireland the population-attributable risk of the 3 common NOD2 variants is estimated to be only a third of that in other Caucasian populations.…”