NOD2 and ATG16L1-A197T Polymorphisms Do Not Confer Risk for Irritable Bowel Syndrome

Abstract

Genomewide association studies demonstrate that genetic polymorphisms in genes associated with alterations in innate immune function (e.g., NOD2 and ATG16L1) confer risk for inflammatory bowel disease (IBD), specifically Crohn's disease (CD). Patients with irritable bowel syndrome (IBS) can also have alterations in their intestinal flora and increased innate immune system activation, potentially leading to low grade inflammation and consequent gastrointestinal symptoms (Ohman et al., Nat Rev Gastroenterol Hepatol 2010). We tested the hypothesis that polymorphisms in NOD2 and ATG16L1 may contribute to the putative derangement in innate immune response underlying IBS pathogenesis. Objectives:We sought to determine if polymorphisms inNOD2 (rs2066847, rs2066844, rs2066845) and ATG16L1A197T (rs2241880), known to confer risk for IBD are also associated with an increased risk of IBS compared to healthy individuals. Methods: Our institutional GI patient database and tissue repository was interrogated to identify subjects with IBS (n=201, 46.4 ±14.5 yr, 66.2%F), CD (n=829; 44.8 ±14.9 yr, 56.9%F), ulcerative colitis (UC, n=325, 45.6 ±15.1 yr, 48%F), or healthy controls (HC) without any gastrointestinal pathology (n=171, 56.6 ±16.0 yr, 52.6%F). Diagnosis of CD and UC required conclusive histopathologic evidence from surgical resection specimens or mucosal biopsy specimens at endoscopy in subjects with compatible clinical and laboratory profiles. Sequenom MassARRAY was used for single nucleotide polymorphism (SNP) genotyping. Inter-group differences in genotypes were assessed by Chi-square analysis. Results: Allele frequencies were in Hardy-Weinberg equilibrium for each of the examined SNPs. As expected, the presence of at least one NOD2 risk allele was significantly more common in CD subjects (267/829, 32.2%) compared to UC (44/325, 13.5%), IBS (27/201, 13.4%), or HC (30/171, 17.5%); p 0.05). There was a significant (p=0.042) difference in G allele frequency of ATG 16L1-A197T when CD subjects (80.3%) were compared with HC (70.1%), or IBS (71.4%). The G allele frequency in ATG 16L1-A197T in UC subjects (75.7%) was similar to HC and IBS (p>0.05). Conclusions: The evaluated polymorphisms in NOD2 and ATGL1 do not conspicuously function as risk alleles for IBS. These findings provide indirect evidence that alterations in the innate immune system described in IBS have a unique yet undiscovered mechanism for pathogenesis and symptom generation; this mechanism may be distinct from that commonly seen and acknowledged in Crohn's disease. Future investigations with genome wide association studies are needed to confirm this hypothesis and further explore the potential role of alleles linked to innate immunity in IBS pathogenesis.