Role of the Solute Carrier Gene Family in Hypertension

描述(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，这些研究的覆盖面如此之广，以至于SLC基因家族的成员没有得到系统的评估。鉴于肾脏通过控制体液容量在血压调节中的主导作用，推测肾脏中表达的126个SLC基因具有特别重要的意义。为了研究肾脏表达的SLC基因中的单核苷酸多态(SNPs)与血压的关系，该应用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和衰老研究(CHARD)联盟的一部分，在120个肾脏表达的SLC基因中总共有7126个SNPs被评估与收缩和舒张压的相关性。基于队列间的复制和结果的荟萃分析，在欧洲血统的成年人中，SLC1A1基因与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。在来自社区动脉粥样硬化风险(ARIC)研究的白人参与者中，将对血压分布上尾部的300名个体和血压分布下部尾部的300名年龄和性别匹配的个体进行重新排序，以调查SLC1A1和SLC6A13。通过重新测序确定的SNP将在所有ARIC白人中进行基因分型，并评估与血压水平的关联。与血压相关的SNPs还将在ARIC非裔美国人以及来自动脉病遗传流行病学网络(Genoa)研究的白人、非裔美国人和西班牙裔高血压同胞中进行研究。最后，将使用细胞模型系统来更好地了解SLC基因的运输特性，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(S)，与公众健康直接相关。这可能会改善抗高血压药物反应的预测，开发简单的实验室测试，以更准确地识别易患高血压的年轻正常血压个体，并更好地了解这种疾病的病因。公共卫生相关性：拟议的研究有助于发现影响血压水平和高血压发生的功能变异(S)，从而与公共健康直接相关。对基因变异的测量可能会比传统方法更好地预测抗高血压药物的疗效，从而对公众健康产生重大影响。此外，这些拟议的研究可能导致开发简单的实验室测试，以更准确地识别易患高血压的年轻正常血压个体，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.