Grant: CIHR Fellowship

Inter-individual genetic variation is a major driver of diversity in response to disease and disease susceptibility, specifically for this project atherosclerosis or arterial plaque formation which leads to heart attack. While differences in the DNA code in gene promoters and protein-coding regions provide obvious prioritization of disease-causing variants, the majority (88%) of genetic variation is in non-coding DNA, suggesting regulatory functions. Prioritization of functional intergenic DNA sequence variation remains challenging due in part to an incomplete understanding of how regulation is achieved at the nucleotide level in different cell types and environmental contexts. Our recent studies of the effects of natural genetic variation on enhancer selection, a functional element within the intergenic region, and function in macrophages provide evidence supporting the concept that acquisition of relatively modest genomic data sets can be used to identify causal variants in a specific cell type. As such, we will be using natural genetic variation as an 'in vivo´ mutagenesis screen to study macrophage affects on atherosclerosis. During thickening of the arterial wall in atherosclerosis, pro-inflammatory cytokines released by the arterial wall alter the environment in a way which promotes cholersterol loaded macrophage to build up and increase the clot size. Here we will study differences in response to the pro-inflammatory cytokine IFN-¿ on signal dependent transcription factor, STAT1 binding. We expect to find genetic variation with the enhancer regions of genes which effects STAT1 binding in response to IFN-¿. Changes will then be correlated with atherogenesis to find a panel of SNPs which may be used to predict predisposition to atherosclerosis.