Effects of SNPs on Gene Regulation in Complex Diseases

DESCRIPTION (provided by applicant): ADAM33 has been identified as an Asthma susceptibility gene. A set of disease-associated single nucleotide polymorphisms (SNPs) have been identified that confer no obvious perturbation on the expressed transcript or the protein that it encodes. We hypothesize that in asthma and other complex diseases, associated SNPs act to perturb the efficiency of DNA/RNA sequence elements, which recruit the proteins that regulate transcription and modulate splicing. Such perturbations in several genes could exert subtle effects on the phenotypic display. Our strategy in Phase I will be to utilize computational approaches to perform a comprehensive search within the ADAM33 gene to predict the location of the transcription regulatory and splicing elements (TRASEs). We will develop a visualization tool to display the TRASEs and the SNPs onto the gene structure of ADAM33. New SNPs will be identified. Statistical analysis will be employed to prioritize the most significant SNP pair haplotypes. We will use the haplotypes to address our hypothesis in Phase II. Our goals in this fast track proposal are to achieve a better understanding of the genetic factors that affect susceptibility to complex diseases and their expression. We will use this knowledge to identify new drug targets that can lead to the development of new therapeutic agents.