Role of the Solute Carrier Gene Family in Hypertension

描述（由申请人提供）：过去十年的几项研究表明，溶质载体（SLC）基因家族成员的遗传变异与血压表型有关。然而，这些研究的覆盖范围是这样的，SLC基因家族的成员没有被系统地评估。考虑到肾脏通过控制体液量在血压调节中所起的主导作用，我们假设在肾脏中表达的126个SLC基因具有特别重要的作用。为了研究肾脏表达SLC基因的单核苷酸多态性（snp）与血压之间的关系，该应用程序利用了欧洲血统成年人的全基因组关联研究（GWAS）数据。作为基因组流行病学心脏与衰老研究（CHARGE）联盟的一部分，研究人员评估了120个肾脏表达的SLC基因中的7126个snp与收缩压和舒张压的关系。基于跨队列复制和结果荟萃分析，SLC1A1基因与欧洲血统成年人的舒张压水平显著相关，SLC6A13基因与收缩压水平显著相关。总之，这些结果表明，两个肾脏表达的SLC基因值得进一步研究它们在血压中的作用。在社区动脉粥样硬化风险（ARIC）研究的白人参与者中，将对来自血压分布上尾的300名个体和来自血压分布下尾的300名年龄和性别匹配的个体进行SLC1A1和SLC6A13的重测序。通过重测序鉴定的snp将在所有ARIC白人中进行基因分型，并评估其与血压水平的关联。与血压相关的snp也将在ARIC非洲裔美国人以及来自动脉病变遗传流行病学网络（GENOA）研究的白人、非洲裔美国人和西班牙裔高血压兄弟姐妹中进行研究。最后，将使用细胞模型系统，以便更好地了解SLC基因所在的运输特性以及这些机制如何受到基因遗传变异的影响。这项拟议的研究通过帮助发现影响血压水平和高血压发生的功能变异，与公共卫生直接相关。这将有可能改善对降压药反应的预测，发展简单的实验室测试，以更准确地识别易患高血压的年轻正常个体，并更好地了解这种疾病的病因。公共卫生相关性：拟议的研究通过帮助发现影响血压水平和高血压发生的功能变异，与公共卫生直接相关。测量遗传变异可以比传统方法更好地预测抗高血压药物反应，从而对公共卫生产生重大影响。此外，这些拟议的研究可能会导致简单的实验室测试的发展，以更准确地识别年轻的血压正常的个体易患高血压，并更好地了解这种疾病的病因。

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.