Alexandra-Chloé Villani, Mathieu Lemire, Marroon Thabane, Alexandre Belisle, Geneviève Geneau, Amit X. Garg, William F. Clark, Paul Moayyedi, Stephen M. Collins, Denis Franchimont, John K. Marshall
Background & Aims:
Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, more than 2300 residents of Walkerton Ontario developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that more than 36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS.
We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2–3 years after the outbreak (n=228, cases) with data from residents that developed gastroenteritis but did not develop PI-IBS (n=581, controls).
Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of SNPs. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P, p =0.0059 and rs5743836, -T1237C, p =0.0250; r2<0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A, p =0.0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C, p=0.0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861, p =0.0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors.
This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with the development of IBS following acute gastroenteritis.