Genetics of the Sodium-Lithium Countertransport

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DESCRIPTION (provided by applicant): The search for genes causing essential hypertension has been ongoing for almost two decades, yet the identification of the effect of these genes and their genomic location has remained elusive. The slow progress in finding genes that harbour susceptibility to essential hypertension has been attributed to the polygenic nature of essential hypertension and the confounding effects of aging and genetic - environmental interactions on the phenotypic expressions of this disorder. Recent studies have indicated that reactive oxygen species (ROS), which are determinants in the aging process, are also major factors in the development and expression of essential hypertension. One of these phenotypes is the sodium lithium countertransport (SLC). As expressed in Epstein-Barr virus (EBV) immortalized lymphoblasts, the SLC is genetically associated and linked with loci harboring clusters of genes encoding enzymes that play key roles in glutathione metabolism. Given that glutathione is at the center of the cellular defense against ROS, these genetic association/linkage findings are in line with the observations that: a) EBV immortalized lymphoblasts from hypertensive donors show an increase in ROS production, b) erythrocytes from hypertensive subjects show low glutathione level and an increase in the oxidized/reduced glutathione ratio, c) thiol metabolism modifies the activity of the SLC, and d) reduced glutathione levels in immortalized lymphoblasts enhances SLC activity. The objectives of this project are as follows: 1. Measure SLC activity in EBV immortalized lymphoblasts from 53 Utah families comprising 561 individuals; 2. Perform genetic analysis using candidate genes and genome-scan approaches to elucidate genes that account for variations in SLC activity; 3. Examine the relationship between SLC activity in EBV immortalized lymphoblasts and cardiovascular indices in the donors; and 4. Explore the mechanisms that link the redox status of immortalized lymphoblasts with the SLC. This will be done by manipulating ROS and glutathione levels in the immortalized lymphoblasts. Results will enhance our understanding of genetic determinants of cardiovascular diseases, including essential hypertension, and provide a mechanistic perspective that links the pathophysiology of essential hypertension to the biology of ROS.