Genetics of risk factor clustering in hypertension

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The spontaneously hypertensive rat (SHR) is the most widely studied genetic model of hypertension and like humans with essential hypertension, exhibits a number of abnormalities in carbohydrate and lipid metabolism that represent risk factors for cardiovascular disease. However, despite extensive research, the basis for the clustering of metabolic risk factors in hypertension remains a mystery. The use of Icongenic and transgenic strains to isolate quantitative trait loci (QTL) that mediate disordered fatty acid and carbohydrate metabolism in the SHR represents a powerful strategy for gaining insight into genetic mechanisms that underlie the clustering of cardiovascular risk factors. Accordingly, the primary objective of this unit is the molecular identification of QTL involved in the clustering of risk factors for cardiovascular disease in spontaneous hypertension. We have identified a region of rat chromosome 10 that is linked to the regulation of circulating levels of fatty acids and insulin in the SHR. Within this chromosome region, we have found that the SHR harbors unique mutations in a transcription factor critically important in the hepatic control of glucose and fatty acid metabolism. Transfer of the target chromosome region from the normotensive Brown Norway strain onto the SHR background has been found to decrease circulating levels of fatty acids and insulin. We hypothesize that a genetic defect causing hepatic overexpression of this transcription factor interacts with a recently identified SHR defect in Cd36 to promote disordered fatty acid and carbohydrate metabolism. Therefore, we will use a combination of transgenic and congenic strains to directly investigate the role of the transcription factor mutations in the pathogenesis of risk factor clustering in the SHR. In the event that these mutations do not contribute to disordered lipid or carbohydrate metabolism in this model, an alternative strategy based on meiotic mapping in congenic strains will be used for molecular identification of QTL linked to the metabolic disturbances in SHR. Although comparisons between humans and rats must be made with caution, it is anticipated that the molecular identification of QTL that promote the clustering of risk factors for cardiovascular disease in the SHR will ultimately shed light on the pathogenesis of disordered carbohydrate and lipid metabolism in patients with essential hypertension.