Abstract
Linkage of IBD to the pericentromeric region of chromosome 16 has been widely confirmed by analyses of multiple populations. The NOD2 gene is located in the peak region of linkage on chromosome 16 and thought to be involved in the activation of nuclear factor (NF) κB in response to bacterial components. Mutations in the NOD2 gene are found to be strongly associated with susceptibility to Crohn's disease (CD). A total of 65 Irish CD families were genotyped to determine if NOD2 mutations conferred susceptibility to CD and the prevalence of these mutations in sporadic and familial forms of the disease. The Irish population is relatively homogenous and thus may provide advantages in genetic studies of complex diseases. We confirmed the IBD1 locus as a susceptibility locus for IBD within the Irish population by linkage analysis followed by linkage disequilibrium studies. No significant evidence of linkage was observed to the previously identified regions on chromosomes 1, 12 and 14. In all, 131 CD affected families were then genotyped for seven of the previously published NOD2 single-nucleotide polymorphisms (SNPs). Allelic transmission distortion was investigated using the pedigree disequilibrium test (PDT). SNP13 (3020insC) was found to be associated with CD (P=0.0186). Patients who possessed a rare allele of SNP8, 12 or 13 presented earlier when compared to patients without rare variants (mean age, 20.1 vs 24 years, P=0.011) and the rare allele of SNP13 was observed to be predominantly linked to ileal disease (P=0.02). This report confirms the importance of NOD2 as a susceptibility gene for CD within the Irish population.
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Acknowledgements
We thank the patients and their families who provided blood samples for this study and the ‘Irish Society of Colitis and Crohn's Disease’ and ‘Irish Ileostomy and Internal Pouch Association’ for explaining the purposes of the study to members. We thank the Irish Society of Gastroenterology. We acknowledge the helpful contribution of Dr Daniel E Weeks, University of Pittsburgh, USA, with linkage analysis and Dr Meredyth P Bass, Duke University Medical Centre, USA, with linkage disequilibrium analysis. This work was supported by the Wellcome Trust (Reference no. 054234/Z/98/Z) and the Irish Health Research Board.
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Bairead, E., Harmon, D., Curtis, A. et al. Association of NOD2 with Crohn's Disease in a homogenous Irish population. Eur J Hum Genet 11, 237–244 (2003). https://doi.org/10.1038/sj.ejhg.5200954
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DOI: https://doi.org/10.1038/sj.ejhg.5200954
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