Association between insertion mutation in NOD2 gene and Crohn's disease inGerman and British populations

Background Genetic predisposition to inflammatory bowel disease (IBD) has b een shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent p opulations. The recently identified NOD2 gene is a good positional and func tional candidate gene since it is located in the region of linkage on chrom osome 16q12, and activates nuclear factor (NF) KB in response to bacterial lipopolysaccharides. Methods We sequenced the coding region of the NOD2 gene and genotyped an in sertion polymorphism affecting the leucine-rich region of the protein produ ct in 512 individuals with IBD from 309 German or British families, 369 Ger man trios (ie, German patients with sporadic IBD and their unaffected paren ts), and 272 normal controls. We then tested for association with Crohn's d isease and ulcerative colitis. Findings Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combine d p<0.0001); the association was confirmed in the 304 German trios with Cro hn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 (95% CI 1.5-4.5)and 4 2.1(4.3-<infinity>), respectively. Interpretation The insertion mutation in the NOD2 gene confers a substantia lly increased susceptibility to Crohn's disease but not to ulcerative colit is.