Asthma is the most common chronic disorder of childhood affecting 9 million children in the United States and is associated with significant morbidity. The pathogenesis of asthma is complex and appears to be the result of both heritable and environmental factors. The Toll-like receptors (TLRs) are a family of innate immunity genes that serve as a critical interface between the immune system and the environment. A single nucleotide polymorphism (SNP) in TLR2 was found to be associated with an increased risk for asthma in children of farmers, but not in non-farmers; however, the mechanisms underlying this association remain unknown. We hypothesize that natural genetic variation in TLR2 affects expression of the gene, thus modifying the TLR2-mediated effects of environmental exposures on immune responses. To test this hypothesis we will start by identifying putative regulatory elements in the 5' UTR of human TLR2 through comparative sequence analysis (phylogenetic shadowing:
Specific Aim 1). We will then characterize these putative regulatory elements for their transcriptional activity and patterns of DNA/protein interactions (Specific Aim 2). Finally, we will determine the function of SNPs located in the regulatory regions of TLR2 (Specific Aim 3). In future work, we will evaluate the association of functional SNPs with susceptibility to asthma and allergic inflammation in phenotypically well-characterized populations available at the ARC. Collectively, these studies will help us understand the molecular mechanisms by which the combination of TLR2 variation and environmental exposures influences the development of asthma.
