engleski

Interaction between endotoxin exposure and Toll like receptor 4 genotypes in relation to asthma amongst Croatian schoolchildren

BACKGROUND: Environmental endotoxin exposure may play an important role in the development of asthma. Toll like receptor 4 (TLR4) is part of the pattern recognition receptor for bacterial endotoxin, and functional variants in this gene confer endotoxin hyporesponsiveness in humans. We investigated whether variants in TLR4 were associated with asthma, and whether domestic endotoxin exposure modified this relationship. METHODS: 423 children with asthma aged 6 to 18 years (cases), were recruited into the study from the local hospital if the following criteria were met: (1) physician-diagnosed asthma, (2) asthma symptoms within the previous 12 months, and (3) use of antiasthma medication ; 414 non-asthmatic controls were randomly selected from the outpatient department or local schools. We collected dust sample from child’s mattress by vacuuming a 1-m2 area for 2 minutes. Endotoxin content was measured by a kinetic limulus assay. Results were expressed as endotoxin load (EU/m2) and level (EU/mg). We genotyped 16 haplotype tagging SNPs in TLR4 (Sequenom) and used multivariate logistic regression analysis to examine the association between asthma, endotoxin exposure and the TLR4 SNPs. RESULTS: All SNPs were in Hardy-Weinberg equilibrium (p>0.01). We found a significant association between two SNPs and asthma (rs1927907 and rs11536889). Carriers of the G allele for rs1927907 were at increased risk for asthma compared with major allele homozygotes (aOR 1.52, 95% CI 1.04-2.21, p=0.03). Homozygotes for C allele in rs11536889 only were significantly more likely to have asthma compared with minor allele carriers (aOR 3.07, 95%CI 1.00-9.71, p=0.04). For the SNP rs11536889 we identified a significant interaction with environmental endotoxin exposure, in that increasing endotoxin load was associated with a marked and significant reduction in the risk of asthma, but only amongst C allele homozygotes. Opposite effect was observed for carriers of the G allele. (p for interaction=0.04). CONCLUSION: We report two novel associations between TLR4 SNPs and asthma among Croatian schoolchildren. In addition, we found a significant interaction between endotoxin exposure and TLR4 SNP and asthma. Thus, in assessing the impact of genetic factors on asthma, it is imperative to consider potential gene–environment interactions.

TLR4; endotoxin; asthma

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