title: The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases.
abstract: The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.forename: D
authors.initials: D
authors.lastname: Franchimont
authors.forename: A
authors.initials: A
authors.lastname: Waliszewska
authors.forename: A
authors.initials: A
authors.lastname: Bitton
authors.forename: A
authors.initials: A
authors.lastname: Cohen
authors.forename: D
authors.initials: D
authors.lastname: Langelier
authors.forename: J
authors.initials: J
authors.lastname: Belaiche
authors.forename: S
authors.initials: S
authors.lastname: Vermeire
authors.forename: L
authors.initials: L
authors.lastname: Farwell
authors.forename: A
authors.initials: A
authors.lastname: Goris
authors.forename: C
authors.initials: C
authors.lastname: Libioulle
authors.forename: N
authors.initials: N
authors.lastname: Jani
authors.forename: T
authors.initials: T
authors.lastname: Dassopoulos
authors.forename: G P
authors.initials: GP
authors.lastname: Bromfield
authors.forename: B
authors.initials: B
authors.lastname: Dubois
authors.forename: J H
authors.initials: JH
authors.lastname: Cho
authors.forename: S R
authors.initials: SR
authors.lastname: Brant
authors.forename: R H
authors.initials: RH
authors.lastname: Duerr
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.forename: M S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: A H
authors.initials: AH
authors.lastname: Steinhart
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.forename: D K
authors.initials: DK
authors.lastname: Podolsky
authors.forename: E
authors.initials: E
authors.lastname: Louis
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
authors.forename: J D
authors.initials: JD
authors.lastname: Rioux
mesh_terms: D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors