Role of the Solute Carrier Gene Family in Hypertension

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

DESCRIPTION (provided by applicant): Several studies in the past decade indicate that genetic variation in members of the solute carrier (SLC) gene family is associated with blood pressure phenotypes. However, the coverage of these studies is such that members of the SLC gene family were not systematically assessed. Given the kidney's dominant role in blood pressure regulation by controlling body fluid volume, it is hypothesized that the 126 SLC genes expressed in the kidney are of particular importance. In order to examine the relationship between single nucleotide polymorphisms (SNPs) in kidney-expressed SLC genes and blood pressure, this application takes advantage of genome-wide association study (GWAS) data in adults of European ancestry. As a part of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium, a total of 7,126 SNPs in 120 kidney-expressed SLC genes were evaluated for an association with systolic and diastolic blood pressure. Based on replication across cohorts and a meta-analysis of results, the SLC1A1 gene was significantly associated with diastolic blood pressure levels and the SLC6A13 gene was significantly associated with systolic blood pressure levels in adults of European ancestry. Together, these results indicate that two kidney-expressed SLC genes warrant additional investigation into their role in blood pressure. In White participants from the Atherosclerosis Risk in Communities (ARIC) study, SLC1A1 and SLC6A13 will be investigated by resequencing in 300 individuals from the upper tail of the blood pressure distribution and in 300 age- and gender-matched individuals from the lower tail of the blood pressure distribution. SNPs identified by resequencing will be genotyped in all ARIC Whites and evaluated for an association with blood pressure levels. SNPs associated with blood pressure will also be investigated in ARIC African Americans and in White, African American and Hispanic hypertensive sibships from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Finally, cellular model systems will be used in order to better understand the transport properties of the SLC genes in which they reside and how these mechanisms are affected by genetic variation in the gene. The proposed research has direct relevance to public health by aiding in the discovery of functional variation(s) influencing blood pressure levels and the occurrence of hypertension. This will potentially leading to improved prediction of antihypertensive medication response, the development of simple laboratory tests to more accurately identify young normotensive individuals predisposed to develop hypertension and to a better understanding of the etiology of this disease. PUBLIC HEALTH RELEVANCE: The proposed research has direct relevance to public health by aiding in the discovery of functional variation(s) influencing blood pressure levels and the occurrence of hypertension. Measurement of genetic variation may improve prediction of antihypertensive medication response beyond conventional approaches, resulting in a significant public health impact. Additionally, these proposed studies may lead to the development of simple laboratory tests to more accurately identify young normotensive individuals predisposed to develop hypertension and to a better understanding of the etiology of this disease.