Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population

Georgia E. Hume, Elizabeth V. Fowler, James Doecke, Lisa A. Simms, Ning Huang, Orazio Palmieri, Lyn R. Griffiths, Timothy H J Florin, Vito Annese, Graham L. Radford-Smith

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)585-590
Number of pages6
JournalInflammatory Bowel Diseases
Volume14
Issue number5
DOIs
Publication statusPublished - May 2008

Fingerprint

Crohn Disease
Haplotypes
Population
Colonic Diseases
Meta-Analysis
Alleles
Genotype
Phenotype
Pattern Recognition Receptors
Toll-Like Receptors
Disease Susceptibility
Ulcerative Colitis
Inflammatory Bowel Diseases
Genes
Immune System
Colon
Mutation

Keywords

  • Crohn's disease
  • Inflammatory bowel disease
  • NOD2
  • TLR4
  • Toll-like receptor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population. / Hume, Georgia E.; Fowler, Elizabeth V.; Doecke, James; Simms, Lisa A.; Huang, Ning; Palmieri, Orazio; Griffiths, Lyn R.; Florin, Timothy H J; Annese, Vito; Radford-Smith, Graham L.

In: Inflammatory Bowel Diseases, Vol. 14, No. 5, 05.2008, p. 585-590.

Research output: Contribution to journalArticle

Hume, GE, Fowler, EV, Doecke, J, Simms, LA, Huang, N, Palmieri, O, Griffiths, LR, Florin, THJ, Annese, V & Radford-Smith, GL 2008, 'Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population', Inflammatory Bowel Diseases, vol. 14, no. 5, pp. 585-590. https://doi.org/10.1002/ibd.20362
Hume, Georgia E. ; Fowler, Elizabeth V. ; Doecke, James ; Simms, Lisa A. ; Huang, Ning ; Palmieri, Orazio ; Griffiths, Lyn R. ; Florin, Timothy H J ; Annese, Vito ; Radford-Smith, Graham L. / Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population. In: Inflammatory Bowel Diseases. 2008 ; Vol. 14, No. 5. pp. 585-590.
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AU - Hume, Georgia E.

AU - Fowler, Elizabeth V.

AU - Doecke, James

AU - Simms, Lisa A.

AU - Huang, Ning

AU - Palmieri, Orazio

AU - Griffiths, Lyn R.

AU - Florin, Timothy H J

AU - Annese, Vito

AU - Radford-Smith, Graham L.

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N2 - 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.

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.

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