S07 IL23R, ATG16L1, IRGM, and OCTNs mRNA expression in inflamed and non-inflamed mucosa of IBD patients

Abstract

In both main forms of Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), intestinal commensal microbiota are thought to trigger the disease in genetically susceptible individuals. Approximately one third of patients with CD have a mutation in the NOD2 gene that encodes an intracellular bacterial pattern-recognition receptor located within Paneth-cells. The maturation of Paneth cells is regulated via the canonical Wnt cascade. The Nkd1 (naked cuticle homologue 1), gene, a Wnt antagonist, is located near NOD2 at 16q12, and it has been found weakly associated with CD in WTCCC dataset (rs8047222 P<1x10-5). Aims: To investigate rs4785433, rs730055, and rs8047222 SNPs of NKD1 and to search for likely correlation with clinical phenotypes in both adult and pediatric onset IBD patients. Methods: 1185 CD patients (670 male) with a mean age at diagnosis of 27 yrs (range 1-80) (334 < 19 yrs at diagnosis), 1385 UC patients (803 male) with a mean age at diagnosis of 31 yrs (range 1-83) (246 < 19 yrs at diagnosis), and 645 healthy controls (HC), were genotyped for NKD1 gene by using the TaqMan allelic discriminationmethod. Genotype frequencies were comparedwith respect to age at diagnosis, disease localization and behaviour (Montreal classification), need of resective surgery, response to medical therapy (steroids, immunosuppressive drugs), and NOD2 status. Results: A significant allele and genotype association of the rs8047222 with UC (P=0.01, OR=0.83, CI=0.73-0.96; P=0.02, OR=0.79; CI=0.65-0.96) was shown, especially in adult-onset cohort (P<0.002). After stratifying the cohort on the basis of NOD2 genotypes (NOD2-=no major variants; NOD2+=at last one variant), a significant genotype association in NOD2patients (P=0.004; OR= 0.74; CI=0.61-0.91) was also demonstrated. No significant difference for either allele and genotype frequencies with rs8047222 was found for CD compared with controls, however, a significant genotype association in NOD2patients (P=0.03, OR=0.77, CI=0.62-0.97) was found. At genotype-phenotype evaluation, a reduced freq uency of distal (E1) vs extensive (E3) colitis in UC (47% vs 78%; P=0.006; OR=0.25, CI=0.09-0.70), and colon (56%) vs ileum localization in CD(65%)(P=0.02, OR=0.69, CI=0.49-0.95) was demonstrated. No significant difference for either allele and genotype frequencies for rs4785433, rs730055 SNPs for IBD was found. Conclusions: The rs8047222 SNP on NKD1 gene has a significant protective role in both UC and CD, possibly influenced by NOD2 status, with interaction with disease localization. Nkd1 might be responsible for the residual linkage at 16q12 locus in NOD2-negative CD patients.