Endotoxin exposure, CD14 and wheeze among farmers: a gene--environment interaction.

Objectives: Endotoxin-exposed workers are at an increased risk of non-atopic asthma and lung-function decline. Genetic variants may influence susceptibility to these effects. The objective of the present study was to assess whether the association between occupational endotoxin exposure and wheeze is modified by innate immunity gene variants.

Methods: Twenty-four single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 4 (TLR4), TLR2, MD2 and MyD88 were genotyped in 408 agricultural workers with spirometry and questionnaire data on asthma symptoms available. Personal airborne endotoxin exposure levels were estimated in 249 exposure measurements.

Results: The association between endotoxin exposure and wheeze was modified by three CD14 SNPs: -260 C/T (rs2569190), -1247 T/C (rs2569191) and -1721 A/G (rs2915863), and one MD2 SNP (rs10808798 T/C). In individuals carrying the CD14 and MD2 major allele variants, the prevalence of wheeze increased with increasing endotoxin concentration, whereas this was the opposite in minor allele homozygotes. Interaction between endotoxin exposure and genotype was statistically significant under the best-fitting recessive model (p=0.05 to 0.006). Correction for multiple comparisons resulted in marginally significant p values for interaction (p<0.06) for CD14 -260 C/T and -1247 T/C, and for MD2 rs10808798 T/C. The CD14 SNPs appeared to modify associations between endotoxin exposure and forced expiratory volume in 1 s in a similar direction (p interaction=0.07 to 0.15).

Conclusions: The association between occupational endotoxin exposure and wheeze in agricultural workers was significantly modified by genetic variants in CD14 and MD2. Our study suggests that carriers of the functional CD14/-260 C allele are more responsive to endotoxin exposure than T allele homozygotes.