Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population.
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.
Hume
Georgia E
GE
Inflammatory Bowel Disease Laboratory, Queensland Institute of Medical Research, Brisbane, Australia. humeone@optusnet.com.au
Fowler
Elizabeth V
EV
Doecke
James
J
Simms
Lisa A
LA
Huang
Ning
N
Palmieri
Orazio
O
Griffiths
Lyn R
LR
Florin
Timothy H J
TH
Annese
Vito
V
Radford-Smith
Graham L
GL
D000293:Adolescent; D000328:Adult; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D011793:Queensland / Q000453:epidemiology; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D004247:DNA