The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease.
BACKGROUND
We investigated the influence of 2 common Toll-like receptor 4 (TLR4) polymorphisms on susceptibility and disease characteristics of Crohn's disease (CD).


METHODS
Genomic DNA from 204 patients with CD and 199 unrelated controls was analyzed for the presence of 2 single nucleotide polymorphisms in the TLR4 gene, resulting in the amino acid substitutions Asp299Gly and Thr399Ile. In addition, the carrier status for the 3 common CD-associated CARD15/NOD2 gene mutations, Arg702Trp, Gly908Arg, and 1007fs, was determined. The frequency of the different genotypes was compared, and a detailed genotype-phenotype correlation was performed.


RESULTS
An almost 2-fold increase in the frequency of the TLR4 Asp299Gly phenotype was observed in patients with CD (14.2%) compared with healthy controls (7.5%, P = 0.038, odds ratio = 2.03). The prevalence of a stricturing phenotype was increased in patients heterozygous for 1 of the TLR4 polymorphisms studied (Asp299Gly, 34.5%; Thr399Ile, 36.7%) compared with patients with wild-type TLR4 (17.1% and 16.7%; P = 0.04 and 0.02, respectively). The presence of the Asp299Gly polymorphism in the absence of CARD15/NOD2 mutations was a particularly strong predictor of the stricturing disease phenotype that was present in 47.4% of the patients with Asp299Gly+/NOD2- compared with 10.1% of the patients with the Asp299Gly-/NOD2+ status (P = 0.0009; P = 0.0004 for Thr399Ile+/NOD2- versus Thr399Ile-/NOD2+). In contrast, there was a trend toward a higher prevalence of the penetrating phenotype in the TLR4-/NOD2+ group (71.6%) compared with the TLR4+/NOD2- group (47.4%, P = 0.059).


CONCLUSIONS
The TLR4 Asp299Gly polymorphism is a risk factor for CD. TLR4 and CARD15/NOD2 mutations may contribute to distinct disease phenotypes.
Brand
Stephan
S
Department of Medicine II, University Hospital Munich-Grosshadern, University of Munich, Munich, Germany. stephan.brand@med.uni-muenchen.de
Staudinger
Tanja
T
Schnitzler
Fabian
F
Pfennig
Simone
S
Hofbauer
Katrin
K
Dambacher
Julia
J
Seiderer
Julia
J
Tillack
Cornelia
C
Konrad
Astrid
A
Crispin
Alexander
A
Göke
Burkhard
B
Lohse
Peter
P
Ochsenkühn
Thomas
T
D000328:Adult; D016022:Case-Control Studies; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011956:Receptors, Cell Surface / Q000235:genetics*; D018709:Statistics, Nonparametric; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors