Role of the Solute Carrier Gene Family in Hypertension

溶质载体基因家族在高血压中的作用

• 批准号: 7727945
• 负责人: Alanna C Morrison
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727945
• 关键词: Accounting; Adult; Affect; African American; Age; Aging; Amino Acids; Antihypertensive Agents; Architecture; Arterial Disorder; Atherosclerosis; Biological Models; Blood Pressure; Body Fluids; Candidate Disease Gene; Cardiovascular system; Cell membrane; Cell model; Communities; Complex; County; DNA Resequencing; Data; Development; Diastolic blood pressure; Disease; Endocrine; Epidemiology; Ethnic group; Etiology; European; Family; Framingham Heart Study; Frequencies; Gender; Gene Family; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Health; Heart; Hispanics; Homeostasis; Hypertension; Individual; Investigation; Ions; Kidney; Knowledge; Laboratories; Lead; Linkage Disequilibrium; Location; Measurement; Meta-Analysis; Methodology; Nervous system structure; Not Hispanic or Latino; Participant; Pattern; Pharmaceutical Preparations; Phenotype; Process; Property; Proteins; Public Health; Research; Research Personnel; Risk; Role; Sampling; Sequence Analysis; Single Nucleotide Polymorphism; Sodium Chloride; Tail; Testing; Variant; Water; base; blood pressure regulation; cohort; genetic epidemiology; genetic linkage analysis; genome wide association study; genome-wide linkage; improved; insight; member; normotensive; population based; prospective; public health relevance; response; solute; sugar

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.

描述（由申请人提供）：过去十年中的几项研究表明，溶质载体（SLC）基因家族成员的遗传变异与血压表型有关。但是，这些研究的覆盖范围是，SLC基因家族的成员没有系统地评估。鉴于肾脏通过控制体液的体积在血压调节中的主要作用，因此假设在肾脏中表达的126个SLC基因特别重要。为了检查肾脏表达的SLC基因和血压中的单核苷酸多态性（SNP）之间的关系，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（电荷）联盟中心脏和衰老研究的一部分，评估了120个肾脏表达的SLC基因中总共7,126个SNP与收缩压和舒张压相关联。基于跨队列的复制和结果的荟萃分析，SLC1A1基因与舒张压水平显着相关，而SLC6A13基因与欧洲血统成年人的收缩压水平显着相关。总之，这些结果表明，两个肾脏表达的SLC基因需要对其在血压中的作用进行额外研究。在社区动脉粥样硬化风险（ARIC）研究中的白人参与者中，将通过重新对300名来自血压分布上尾的人以及300岁的年龄和性别匹配的个体从血压分布的下部尾部进行重新定制，以研究SLC1A1和SLC6A13。通过重新取证确定的SNP将在所有ARIC白色中进行基因分型，并评估与血压水平的关联。与血压相关的SNP还将在ARIC非洲裔美国人和白人，非裔美国人和西班牙裔高血压疾病中进行研究。最后，将使用细胞模型系统，以更好地了解其所在的SLC基因的转运特性以及这些机制如何受到基因遗传变异的影响。拟议的研究通过协助发现影响血压水平和高血压发生的功能变异来直接与公共卫生相关。这可能会导致改善对降压药反应的预测，发展简单的实验室测试，以更准确地识别易于发展高血压的年轻正常人，并更好地理解这种疾病的病因。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化，与公共卫生有直接相关。遗传变异的测量可以改善降压药反应的预测，而不是常规方法，从而产生了重大的公共卫生影响。此外，这些提出的研究可能导致简单的实验室测试的发展，以更准确地识别易于发展高血压的年轻正常人，并更好地理解该疾病的病因。