Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1

In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6.We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele.Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.Exposure to endotoxin, a component of the gram negative bacterial cell wall, has been associated with a lower prevalence of asthma symptoms, and a decreased risk of allergic sensitization in childhood [1-3]. Children exposed to the farming environment, where microbial exposures are high, have lower rates of asthma and allergies [4,5]. The ability of endotoxin to modulate innate immune response may explain its protective effects. Endotoxin binds to the TLR4 receptor on antigen presenting cells, initiating, through an MYD88 dependent pathway, the production of IL-12. Secretion of IL-12 promotes the differentiation of na？ve T cells into Th1 cells that blunt the Th2 response implicated in asthma and allergic disease [6]. T-regulatory cell function is enhanced in the presence of endotoxin, suggesting an alternative protective mechanism for this gram-negative bacterial component [6,7]. The effects of environmental endotoxin on allergic disease most likely depend upon timing, dose and