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Genetic investigation of inflammatory bowel disease and post-infectious irritable bowel syndrome : the contribution of innate immunity candidate risk variants

The gastro-intestinal (GI) tract represents the largest surface of the body and is continuously exposed to the microbial environment. In such anatomy, the survival of the host requires that the intestinal microbial flora be contained without excessive immune-reactivity to commensal bacteria while retaining the ability to respond to episodic pathogens. The discriminative recognition between beneficial commensal bacteria and potentially harmful pathogens demands an accurate interpretation by the GI mucosal immune system. Any defects in the processes of innate immune recognition and killing may lead to the development and perpetuation of chronic intestinal inflammation, namely inflammatory bowel disease (i.e. Crohn's disease (CD) and ulcerative colitis (UC)) and post-infectious irritable bowel syndrome (PI-IBS). The aim of ours studies was to evaluate the contribution of candidate genes, involved in the homeostasis and regulation of the intestinal innate immune response, to the susceptibility to CD, DC, and PI-IBS. In the first phase, we describe functional and genetic association results supporting NLRP3, encoding NALP3/cryopyrin, as a novel CD susceptibility gene. We subsequently report that the MEFV gene, encoding pyrin, known to interact with and be involved in the same pathway as NALP3/cryopyrin, does not contribute to CD and DC susceptibility. No CD or DC additional associations were observed upon NLRP3-MEFV gene-gene interaction analyses. In the third phase, we report the first association study evaluating genetic determinants for PI-IBS, using the well-characterized Walkerton population cohort. We uncovered variants in the TLR9, CDH1, and IL6 regions associated with PI-IBS susceptibility. These results are in keeping with the pathophysiologic changes observed in patients with PI-IBS, which include increased intestinal permeability and intestinal immune activation. / Overall, these results contribute to a better understanding of the genetic susceptibility to CD, DC and PI-IBS and shed light on new pathogenic signaling pathways in the development of these diseases.

Identiferoai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.115888
Date January 2009
CreatorsVillani, Alexandra-Chloé.
PublisherMcGill University
Source SetsLibrary and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada
LanguageEnglish
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation
Formatapplication/pdf
CoverageDoctor of Philosophy (Division of Experimental Medicine.)
RightsAll items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated.
Relationalephsysno: 003132373, proquestno: AAINR66673, Theses scanned by UMI/ProQuest.

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