Abstract
BackgroundThe 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 FindingsGenomic 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 <10−10. The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D'>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/SignificanceThe NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by an exaggerated immune response of the intestinal mucosa and a dysfunctional epithelial barrier [1,2,3,4]
The novel NOD2 variants rs2066843 and rs2076756 are associated with susceptibility to CD but not to UC In the controls, the genotype frequencies of the SNPs rs2066843 and rs2076756 were in agreement with the predicted HardyWeinberg equilibrium
Significant differences in the allele frequencies of the SNPs rs2066843 and rs2076756 were observed in CD patients but not in UC patients compared to healthy controls
Summary
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by an exaggerated immune response of the intestinal mucosa and a dysfunctional epithelial barrier [1,2,3,4]. The identification of nucleotide-binding oligomerization domain 2 (NOD2, GeneID: 64127), known as caspase recruitment domain-containing protein 15 (CARD15) as the first susceptibility gene in CD in 2001 [5,6] has provided significant new insights in the pathogenesis of IBD focusing on the genetic background of innate immune response and interaction with bacterial antigens [7,8,9,10]. Large genotypephenotype analyses by us [21,22] and others [23,24,25] demonstrated a significant association of NOD2 variants with ileal involvement, stricturing phenotype and early disease onset in CD patients. 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
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