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The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

Genes & Immunity volume 8, pages 387–397 (2007)Cite this article

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.

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Acknowledgements

We thank patients with IBD and their families for their collaboration on this project. We also thank Drs Ramnik Xavier and Philippe Goyette for their helpful comments on the manuscript. PLD is the William C Fowler scholar in Multiple Sclerosis and is supported by an NINDS K08 grant as well as the Clinical Investigator Training Program: Harvard-MIT Health Sciences and Technology Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. The authors have no conflicts of interest to report. EL is supported by the FNRS Belgium. AG is a postdoctoral fellow of the Fund for Scientific Research-Flanders and BD is supported by the University Research Council of the University of Leuven, Belgium. JDR is supported by grants from the NIDDK and the CCFA. The authors have no conflict of interest to report.

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Authors and Affiliations

  1. Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA

    P L De Jager, A Waliszewska, D A Hafler & J D Rioux

  2. Program in Medical & Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    P L De Jager, A Waliszewska, L Farwell, M J Daly, D A Hafler & J D Rioux

  3. Division of Gastroenterology, Department of Internal Medicine, Montreal General Hospital, McGill University, Montreal, Quebec, Canada

    D Franchimont

  4. Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada

    A Bitton

  5. Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada

    A Cohen

  6. Centre Hospitalier Universitaire de Sherbrooke – Hopital Fleurimont, Sherbrooke, Quebec, Canada

    D Langelier

  7. Division of Gastroenterology, CHU, University of Liege, Liege, Belgium

    J Belaiche & E Louis

  8. Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium

    S Vermeire

  9. Section of Experimental Neurology, University of Leuven, Leuven, Belgium

    A Goris & B Dubois

  10. Centre for Biomedical Integrative Genoproteomics, University of Liege, Liege, Belgium

    C Libioulle

  11. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    N Jani & R H Duerr

  12. Department of Medicine, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University, Baltimore, MD, USA

    T Dassopoulos & S R Brant

  13. Department of Medicine, University of Chicago, Chicago, IL, USA

    G P Bromfield

  14. Departments of Medicine and Genetics, IBD Center, Section of Gastroenterology, Yale University, New Haven, CT, USA

    J H Cho

  15. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    S R Brant

  16. Division of Medical Genetics, Department of Medicine, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    H Yang & J I Rotter

  17. Division of Gastroenterology, Mount Sinai Hospital IBD Center, University of Toronto, Toronto, Ontario, Canada

    M S Silverberg & A H Steinhart

  18. Department of Medicine, Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    D K Podolsky

  19. Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada

    J D Rioux

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  1. P L De Jager
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  2. D Franchimont
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Quebec IBD Genetics Consortium and NIDDK IBD Genetics Consortium

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Correspondence to J D Rioux.

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PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)

dbSNP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Snp)

UCSC Genome Browser (http://genome.ucsc.edu/)

LocusView (http://www.broad.mit.edu/mpg/locusview/)

Haploview (www.broad.mit.edu/mpg/haploview/)

Genetic Power calculator (http://statgen.iop.kcl.ac.uk/gpc/)

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De Jager, P., Franchimont, D., Waliszewska, A. et al. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun 8, 387–397 (2007). https://doi.org/10.1038/sj.gene.6364398

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  • DOI: https://doi.org/10.1038/sj.gene.6364398

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