Integrative genetic approaches to Atherosclerosis

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Common human diseases result from the interplay of many genes and the environment. During the past few years, genome-wide association studies (GWAS) have succeeded in identifying many novel loci underlying cardiovascular disease traits. However, the genes are generally identified out of context and, in most cases, a very small fraction of the genetic component has been identified, even in very large studies. Our laboratory is employing a systems genetic approach to understand the higher order interactions in complex diseases. This involves the integration of DNA variation, global gene expression, and clinical phenotypes. In systems genetics, transcript levels are examined as a function of genetic variation, not simply in cases versus controls. We propose to apply this systems genetics approach to attempt to better understand the association between a haplotype on human chromosome 9p21 and coronary artery disease susceptibility. In Aim 1, we propose to characterize the patterns of expression of the genes in the 9p21 region in tissue culture in human cells and in mouse genetic crosses. In Aim 2, we analyze in detail the effects of the susceptibility alleles on RNA splicing and we examine the possibility the locus encodes microRNAs capable of regulating gene expression. In Aim 3 we utilize a series of transgenic/knockout models to test the role of genes at the locus and to validate findings from Aims 1 and 2.