Stroke is the third leading cause of death in the United States and is frequently associated with long-term disability. The stroke-prone spontaneously hypertensive rat (SHRSP), which was developed by selective breeding from the spontaneously hypertensive rat (SHR), represents a suitable model of hypertension-associated stroke. Stroke occurrence is influenced by the complex interaction of multiple genes and environmental factors. The role of dietary sodium and potassium in modulating the onset of stroke has been well documented both in humans and animal models. In the SHRSP, diet high in sodium and low in potassium accelerates the development of stroke. In contrast, a high intake of potassium markedly protects against stroke occurrence, even though blood pressure levels remain unchanged. We have applied a gene expression profiling strategy using oligonucleotide micro-arrays to identify genes and gene pathways implicated in the development of stroke in this animal model. Because gene expression profiles uniquely and comprehensively reflect the complex and dynamic interaction of a defined set of genes with the environment, characterization of gene expression changes induced by dietary perturbations among inbred rat strains differing in their genetic propensity to develop stroke will provide clues on the mechanisms governing the interaction of stroke susceptibility genes with the dietary factors known to influence the disease process. The proposed application will focus on identifying stroke-susceptibility genes interacting with dietary salt intake to influence the initiation of stroke events in the SHRSP by comparing the gene expression profiles in the cortical regions of the brain of male SHRSPs and SHRs exposed to a regular vs. stroke- permissive diet. We will then identify genetic variants in these expressional candidate genes, as well as a panel of selected biological/positional candidate genes. We will assess the cosegregation of the genetic variants with stroke latency in the F2 progeny of SHRSP x SHR parental crosses. In addition, we will examine whether the relationship between genetic variants in candidate genes and variation in stroke latency in the F2 is modified by dietary factors. We will finally evaluate the potential relevance of a paradigm of stroke causation established in an experimental model to human disease. Specifically, we will characterize sequence variation within or near the human homologue of ten genes identified in this proposal and determine whether variation in these genes is associated with stroke incidence in a large population-based sample of individuals participating in the Atherosclerosis Risk in Communities (ARIC) study. We will also identify and characterize DNA variation in a panel of selected stroke-candidate human genes and test whether variation in these genes is associated with risk of developing a stroke in the ARIC sample.
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