engleski

Genetic variants in endotoxin pathway, endotoxin exposure and asthma exacerbations

Background: Environmental endotoxin exposure has diverse effects on asthma: exposure during early life may be protective against asthma development, but amongst patients with established disease current exposure induce symptoms and increase asthma severity. The endotoxin response pathway has the complex of innate immunity receptors (CD14/TLR4/ MD2) at the core. Among patients with asthma, we investigated the association between genetic variants in endotoxin pathway and severe asthma exacerbations. In addition, we evaluated the effect of endotoxin exposure in the context of genetic variants. Method: Four hundred and twenty- three children with asthma aged 5–18 years, 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 asthma medication. Data on hospital admission with severe asthma exacerbations were extracted from medical records. We collected dust sample from child’s mattress by vacuuming a 1 m2 area for 2 min. Endotoxin content was measured by a kinetic limulus assay. We genotyped 30 haplotype tagging SNPs (5 SNPs in CD14, 16 SNPs in TLR4 and 9 SNPs in MD2). Results: We observed one significant association between genetic variant on CD14 (rs5744455) and severe asthma exacerbations which remained significant after false discovery rate (FDR) correction [CC vs CT + TT, OR (95% CI), 2.42 (1.28–4.59), P = 0.006, FDR P value = 0.02). We observed significant interactions between 11 SNPs and environmental endotoxin exposure in relation to severe asthma exacerbation (4 in CD14, 4 in MD2 and 3in TLR4). Four described interactions (rs4914, rs2915862 and rs5744455 in CD14 and rs17226566 in MD2) remained significant after correction for multiple testing (P < 0.05). For example, endotoxin exposure increased the risk of hospital admission amongst patients with asthma who were T allele homozygotes in CD14 SNP rs5744455, with no effect of exposure amongst C allele carriers (P for interaction = 0.02, FDR p value = 0.04). Conclusion: We demonstrated that one genetic variant in CD14 (rs5744455) was associated with severe asthma exacerbation. In addition, interactions between 4 genetic variants in endotoxin pathway (3 in CD14 and 1 in MD2) and endotoxin exposure in relation to asthma exacerbation remained significant after FDR correction

CD14; MD2; TLR4; asthma exacerbations

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