Elsevier

The Lancet

Volume 357, Issue 9272, 16 June 2001, Pages 1925-1928
The Lancet

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

https://doi.org/10.1016/S0140-6736(00)05063-7Get rights and content

Summary

Background

Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) κB in response to bacterial lipopolysaccharides.

Methods

We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis.

Findings

Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0·0001); the association was confirmed in the 304 German trios with Crohn'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 42·1 (4·3−∞), respectively.

Interpretation

The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.

Introduction

Epidemiological and genetic linkage studies have shown the cause of inflammatory bowel disease (IBD) and its constituent clinical phenotypes Crohn's disease and ulcerative colitis to have a genetic component. Epidemiological investigations have consistently shown familial clustering1 and an increased concordance of the IBD phenotype in monozygotic twins.2, 3

An IBD1 susceptibility region on chromosome 16 was detected by genome-wide linkage analysis,4 and this finding has been replicated in several independent populations,5, 6, 7 and by the International IBD Consortium.8 This region of linkage is therefore the most widely and consistently replicated in IBD.

Previous pathophysiological research has shown that signalling by tumour necrosis factor and activation of nuclear factor (NF) κB in mononuclear cells have a key role in IBD.9, 10 Therefore, genetic variants that would lead to increased or persistent NFκB activation are of particular interest. NOD2—a member of the NOD1/APAF1 gene family—has been identified and mapped to chromosome 16q12·11 This gene family has a role in inflammatory responses to bacterial triggers, especially lipopolysaccharides, through activation of NFκB,12, 13 and a submission to an electronic database suggested the presence of NOD2 polymorphisms in Crohn's disease (NCBI locus ID 64127).

NOD2 is expressed exclusively in monocytes. Creation of truncation variants of the protein product in the original identification study11 showed that only the deletion of the leucine-rich region leads to increased activation of NFκB. We therefore selected this leucine-rich region as a functional and positional candidate region for further exploration.

Section snippets

Participants

The family cohorts investigated in this study were recruited by an international group of IBD investigators at the Charité University Hospital (Berlin, Germany), the Department of General Internal Medicine at the Christian- Albrechts-Universität (Kiel, Germany), St Mark's, Guy's and King's College Hospitals (London, UK), and other European centres. These cohorts have been used in previous studies within the collaborative group.5, 14, 15, 16 We also recruited German patients with sporadic IBD

Results

512 affected individuals from 309 multiplex families of German or British descent, 369 German patients with sporadic IBD, and 272 healthy controls were genotyped for the C-insertion mutation in exon 11 of NOD2 (table 1). For the Crohn's disease phenotype, family-based tests showed a significant association for the British and German cohorts alone, and for both cohorts combined (table 2). A confirmatory analysis in the German trios (sporadic cases and their parents) yielded a similar result.

Discussion

The results of our study provide evidence for association of a NOD2 frameshift mutation with Crohn's disease. Consistent results were obtained in two different populations by means of family-based association analyses (estimation of transmission distortion) and case-control analysis. The mutation is quite rare—only about 6·5% of Crohn's disease patients are homozygous for it. We estimate that about 18% of the genetic risk in the population can be attributed to this mutation. The NOD2 mutation

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