Novel NOD2 Haplotype Strengthens the Association Between TLR4 Asp299gly and Crohn's Disease in an Australian Population.

Hume, G.E., Fowler, E.V., Doecke, J., Simms, L.A., Huang, N., Palmieri, O., Griffiths, L.R., Florin, Timothy H., Annese, V. and Radford-Smith, G.L. (2008) Novel NOD2 Haplotype Strengthens the Association Between TLR4 Asp299gly and Crohn's Disease in an Australian Population.. Inflammatory Bowel Diseases, 14 5: 585-590. doi:10.1002/ibd.20362


Author Hume, G.E.
Fowler, E.V.
Doecke, J.
Simms, L.A.
Huang, N.
Palmieri, O.
Griffiths, L.R.
Florin, Timothy H.
Annese, V.
Radford-Smith, G.L.
Title Novel NOD2 Haplotype Strengthens the Association Between TLR4 Asp299gly and Crohn's Disease in an Australian Population.
Formatted title
Novel NOD2 Haplotype Strengthens the Association Between TLR4 Asp299gly and Crohn's Disease in an Australian Population.
Journal name Inflammatory Bowel Diseases   Check publisher's open access policy
ISSN 1078-0998
Publication date 2008-05-01
Sub-type Article (original research)
DOI 10.1002/ibd.20362
Open Access Status
Volume 14
Issue 5
Start page 585
End page 590
Total pages 6
Place of publication United States of America
Publisher Wiley
Language eng
Subject C1
920105 Digestive System Disorders
110307 Gastroenterology and Hepatology
110311 Medical Genetics (excl. Cancer Genetics)
Abstract AB Background: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. Methods: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype-phenotype relationships were also sought. Meta-analysis was conducted via RevMan. Results: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). Conclusions: TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes.
Formatted abstract
Background: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis.
Methods: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype-phenotype relationships were also sought. Meta-analysis was conducted via RevMan.
Results: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001).
Conclusions: TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes.
Keyword Crohn's disease
Inflammatory bowel disease
NOD2
TLR4
Toll-like receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Tue, 07 Apr 2009, 21:58:46 EST by Joanne PRESTON on behalf of School of Medicine