title: Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis.
abstract: OBJECTIVE
  Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS.
  
  
  METHODS
  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 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls).
  
  
  RESULTS
  Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .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.
  
  
  CONCLUSIONS
  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 development of IBS following acute gastroenteritis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, McGill University, Montréal, Québec, Canada. alexandra-chloe.villani@mail.mcgill.ca
authors.forename: Alexandra-Chloé
authors.initials: AC
authors.lastname: Villani
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Marroon
authors.initials: M
authors.lastname: Thabane
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belisle
authors.forename: Geneviève
authors.initials: G
authors.lastname: Geneau
authors.forename: Amit X
authors.initials: AX
authors.lastname: Garg
authors.forename: William F
authors.initials: WF
authors.lastname: Clark
authors.forename: Paul
authors.initials: P
authors.lastname: Moayyedi
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Collins
authors.forename: Denis
authors.initials: D
authors.lastname: Franchimont
authors.forename: John K
authors.initials: JK
authors.lastname: Marshall
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D004196:Disease Outbreaks; D005260:Female; D005759:Gastroenteritis / Q000150:complications*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D043183:Irritable Bowel Syndrome / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014871:Water Microbiology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D015850:Interleukin-6; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9