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

P. L. De Jager; D. Franchimont; A. Waliszewska; A. Bitton; A. Cohen; D. Langelier; J. Belaiche; S. Vermeire; L. Farwell; A. Goris; C. Libioulle; N. Jani; T. Dassopoulos; G. P. Bromfield; B. Dubois; J. H. Cho; S. R. Brant; R. H. Duerr; H. Yang; J. I. Rotter; M. S. Silverberg; A. H. Steinhart; M. J. Daly; D. K. Podolsky; E. Louis; D. A. Hafler; J. D. Rioux

doi:10.1038/sj.gene.6364398

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

P. L. De Jager, D. Franchimont, A. Waliszewska, A. Bitton, A. Cohen, D. Langelier, J. Belaiche, S. Vermeire, L. Farwell, A. Goris, C. Libioulle, N. Jani, T. Dassopoulos, G. P. Bromfield, B. Dubois, J. H. Cho, S. R. Brant, R. H. Duerr, H. Yang, J. I. RotterM. S. Silverberg, A. H. Steinhart, M. J. Daly, D. K. Podolsky, E. Louis, D. A. Hafler, J. D. Rioux

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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.

Original language	English (US)
Pages (from-to)	387-397
Number of pages	11
Journal	Genes and immunity
Volume	8
Issue number	5
DOIs	https://doi.org/10.1038/sj.gene.6364398
State	Published - Jul 2007
Externally published	Yes

ASJC Scopus subject areas

Immunology
Genetics
Genetics(clinical)

Access to Document

10.1038/sj.gene.6364398

Cite this

De Jager, P. L., Franchimont, D., Waliszewska, A., Bitton, A., Cohen, A., Langelier, D., Belaiche, J., Vermeire, S., Farwell, L., Goris, A., Libioulle, C., Jani, N., Dassopoulos, T., Bromfield, G. P., Dubois, B., Cho, J. H., Brant, S. R., Duerr, R. H., Yang, H., ... Rioux, J. D. (2007). The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes and immunity, 8(5), 387-397. https://doi.org/10.1038/sj.gene.6364398

De Jager, PL, Franchimont, D, Waliszewska, A, Bitton, A, Cohen, A, Langelier, D, Belaiche, J, Vermeire, S, Farwell, L, Goris, A, Libioulle, C, Jani, N, Dassopoulos, T, Bromfield, GP, Dubois, B, Cho, JH, Brant, SR, Duerr, RH, Yang, H, Rotter, JI, Silverberg, MS, Steinhart, AH, Daly, MJ, Podolsky, DK, Louis, E, Hafler, DA & Rioux, JD 2007, 'The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases', Genes and immunity, vol. 8, no. 5, pp. 387-397. https://doi.org/10.1038/sj.gene.6364398

@article{71e50e80b8104d359c144260759a9b74,

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.",

author = "{De Jager}, {P. L.} and D. Franchimont and A. Waliszewska and A. Bitton and A. Cohen and D. Langelier and J. Belaiche and S. Vermeire and L. Farwell and A. Goris and C. Libioulle and N. Jani and T. Dassopoulos and Bromfield, {G. P.} and B. Dubois and Cho, {J. H.} and Brant, {S. R.} and Duerr, {R. H.} and H. Yang and Rotter, {J. I.} and Silverberg, {M. S.} and Steinhart, {A. H.} and Daly, {M. J.} and Podolsky, {D. K.} and E. Louis and Hafler, {D. A.} and Rioux, {J. D.}",

note = "Funding Information: 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.",

year = "2007",

month = jul,

doi = "10.1038/sj.gene.6364398",

language = "English (US)",

volume = "8",

pages = "387--397",

journal = "Genes and immunity",

issn = "1466-4879",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

AU - De Jager, P. L.

AU - Franchimont, D.

AU - Waliszewska, A.

AU - Bitton, A.

AU - Cohen, A.

AU - Langelier, D.

AU - Belaiche, J.

AU - Vermeire, S.

AU - Farwell, L.

AU - Goris, A.

AU - Libioulle, C.

AU - Jani, N.

AU - Dassopoulos, T.

AU - Bromfield, G. P.

AU - Dubois, B.

AU - Cho, J. H.

AU - Brant, S. R.

AU - Duerr, R. H.

AU - Yang, H.

AU - Rotter, J. I.

AU - Silverberg, M. S.

AU - Steinhart, A. H.

AU - Daly, M. J.

AU - Podolsky, D. K.

AU - Louis, E.

AU - Hafler, D. A.

AU - Rioux, J. D.

N1 - Funding Information: 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.

PY - 2007/7

Y1 - 2007/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34547459989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547459989&partnerID=8YFLogxK

U2 - 10.1038/sj.gene.6364398

DO - 10.1038/sj.gene.6364398

M3 - Article

C2 - 17538633

AN - SCOPUS:34547459989

SN - 1466-4879

VL - 8

SP - 387

EP - 397

JO - Genes and immunity

JF - Genes and immunity

IS - 5

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this