Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations

Abstract

The first gene associated with Crohn disease (CD) has been identified as CARD15 (16q12). Three variants, R702W, G908R and 1007fsinsC are strongly and independently associated with the disease. A second gene, conveying a smaller risk for inflammatory bowel disease (IBD), has been identified as DLG5 (10q23). We assess the frequency of the CARD15 SNPs and of the R30Q mutation in DLG5 and their contribution to the development of CD in a cohort of unrelated IBD patients (151 CD, 325 ulcerative colitis (UC)) and healthy controls (236) from South-east Norway (IBSEN cohort). Genotype-based tests of population differentiation using 23 SNPs across CARD15, together with estimates of F ST , indicated that the German and Norwegian background populations could be differentiated at the CARD15 locus. The Norwegian and German CD samples exhibited particularly strong differentiation at the three predisposing loci and those marking their background haplotype. There were significantly lower frequencies of the CARD15 SNPs and no significant association with CD in the Norwegian samples. Only a marginal association was observed for the subphenotypes ileitis and ileocolitis vs colitis (P ¼ 0.048). The population attributable risk percentage (PAR%) for CARD15 variants in the Norwegian cohort is the lowest reported for a European population (1.88%), except Iceland. Similarly, the DLG5 variant showed no association with CD or IBD, however, there was a negative correlation with stricture (P ¼ 0.035). The present results are consistent with an emerging pattern of a low frequency of the CARD15 variants in Northern countries where the prevalence of IBD is greatest.

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis

“…The PAR relating to the common three NOD2/CARD15 mutations in Northern Europe is significantly lower than Southern Europe. 4 This study demonstrates that there are no other mutations within the gene that account for this low PAR in the Scottish population, replicating the data from Medici et al 45 in a Norwegian population. The identification of a common 'Northern European' susceptibility gene remains to be explored.…”

Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients

“…Three major polymorphisms in the CARD15 gene, R702W, G908R and 1007fs, were confirmed to be associated with susceptibility to Caucasian CD patients by independent groups (Ahmad et al 2002;Lesage et al 2002), even though the frequencies of these variants were quite different between ethnically divergent populations. Among CD patients of European ancestry, CARD15 variants were more significantly associated in the Central European population (Hugot et al 2001;Ahmad et al 2002;Lesage et al 2002) than in the North European population (Paavola-Sakki et al 2003;Arnott et al 2004;Medici et al 2006). The absence of the variants were widely known in Asia; Japanese (Yamazaki et al 2002), Korean (Croucher et al 2003) and Chinese populations (Leong et al 2003).…”

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…Present approaches have not been able to discern whether these other genes or the class Ⅱ genes are the true risk genes in the HLA locus. [79][80][81][82] , multiple polymorphisms in the MDR1/ABCB1 gene on chromosome 7q [83][84][85][86][87][88][89][90][91][92] , and polymorphisms in the DLG5 gene on chromosome 10q [70,[93][94][95][96][97][98][99][100][101][102] . (See section C.4.1.)…”