1. ¹Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
2. ²Program in Medical & Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
3. ³Division of Gastroenterology, Department of Internal Medicine, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
4. ⁴Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
5. ⁵Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada
6. ⁶Centre Hospitalier Universitaire de Sherbrooke – Hopital Fleurimont, Sherbrooke, Quebec, Canada
7. ⁷CHU, Division of Gastroenterology, University of Liege, Liege, Belgium
8. ⁸Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
9. ⁹Section of Experimental Neurology, University of Leuven, Leuven, Belgium
10. ¹⁰Centre for Biomedical Integrative Genoproteomics, University of Liege, Liege, Belgium
11. ¹¹Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
12. ¹²Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
13. ¹³Department of Medicine, University of Chicago, Chicago, IL, USA
14. ¹⁴IBD Center, Section of Gastroenterology, Departments of Medicine and Genetics, Yale University, New Haven, CT, USA
15. ¹⁵Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
16. ¹⁶Division of Medical Genetics, Department of Medicine, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
17. ¹⁷Division of Gastroenterology, Mount Sinai Hospital IBD Center, University of Toronto, Toronto, Ontario, Canada
18. ¹⁸Gastrointestinal Unit, Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
19. ¹⁹Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada

Correspondence: Dr JD Rioux, Montreal Heart Institute, University of Montreal, 5000 Belanger Street, Rm S-6400, Montreal, Quebec, Canada H1T 1C8. E-mail: rioux@broad.mit.edu

Received 13 December 2006; Revised 16 April 2007; Accepted 17 April 2007; Published online 31 May 2007.

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.