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The NOD2 Single Nucleotide Polymorphisms rs2066843 and rs2076756 Are Novel and Common Crohn's Disease Susceptibility Gene Variants

2010; Public Library of Science; Volume: 5; Issue: 12 Linguagem: Inglês

10.1371/journal.pone.0014466

1932-6203

Jürgen Glas, Julia Seiderer, Cornelia Tillack, Simone Pfennig, Florian Beigel, Matthias Jürgens, Torsten Olszak, Rüdiger P. Laubender, Maria Weidinger, Bertram Müller-Myhsok, Burkhard Göke, Thomas Ochsenkühn, Peter Lohse, Julia Diegelmann, Darina Czamara, Stephan Brand,

Tuberculosis Research and Epidemiology

Background The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. Methodology/Principal Findings Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10−5, OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10−6; OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values 0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10−16) and behaviour (p = 0.02) were significantly associated with the need for surgery. Conclusion/Significance The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.