Genetic Determinants of Sodium Retention

描述（由申请人提供）：高血压影响近5000万美国人；它是心脏病、中风和肾衰竭的主要危险因素。其病因尚不清楚，虽然钠（Na）潴留是一个潜在的易感性因素。在目前的应用中，我们试图通过一种策略来确定高血压的新机制，在这种策略中，我们确定了肾脏中的钠转运蛋白，这解释了为什么黑人比白人保留更多的钠。基于令人信服的证据，我们将研究与黑人中na潴留增加有关的肾元沿线的三个位点：在Specific Aim 1中，厚升肢中的Na-K-2CI共转运蛋白；在特异性靶2中，远曲小管中噻嗪类药物敏感的Na-Cl共转运体；特异性Aim 3为皮质集管上皮Na通道。利用这些转运蛋白及其调节因子的遗传标记，我们将检验在任何位点上转运蛋白功能的增加有助于黑人中Na的更大保留的假设。研究队列包括黑人和白人，其中一些人被跟踪测量血压（BP）和体型（每6-12个月）长达15年，为我们提供了重要的血压调节表型。受试者年轻（平均年龄20岁），除少数例外，血压正常（其中许多人可能处于高血压前期）。它们没有年龄相关和高血压相关的混杂影响，也没有抗高血压药物的作用。因此，我们探索了早期外显率的表型，这些外显率在老年高血压患者中可能不太明显。在普通临床研究中心进行的一项新的干入性研究-生理盐水/利尿剂方案-允许表型（肾素和醛固酮水平和血压）的产生，以响应钠平衡的主要变化。在特定目标2的主题子集中。我们还评估了血压对小剂量噻嗪类利尿剂的敏感性，以验证黑人比白人具有更活跃的噻嗪类敏感Na-Cl共转运体的假设。利用单核苷酸多态性在基因的na -重吸收系统，我们检查连锁不平衡与表型。将招募更多的家庭成员（父母和兄弟姐妹），将关联研究扩展到传播不平衡测试，并允许单倍型的产生。总之，通过探索与白人相比，黑人钠潴留增加的候选位点，我们试图确定常见形式高血压的新机制。

DESCRIPTION (provided by applicant): Hypertension affects nearly 50 million Americans; it is a major risk factor for heart disease, stroke and renal failure. Its etiology is mostly unknown, although sodium (Na) retention is a factor underlying much of the susceptibility. In the present application, we seek to identify new mechanisms for hypertension using a strategy where we identify the Na transporters in kidney that account for why blacks retain more Na than whites. Three sites along the nephron will be studied based on compelling evidence that they are linked to the increased Na-retention in blacks: In Specific Aim 1, the Na-K-2CI cotransporter in thick ascending limb; in Specific Aim 2, the thiazide-sensitive Na-Cl cotransporter in distal convoluted tubule; and in Specific Aim 3, the epithelial Na channel in cortical collecting duct. Using genetic markers for these transporters and their regulators, we will test the hypothesis that an increase in the transporter function at any of the sites contributes to the greater retention of Na in blacks. The study cohort consists of blacks and whites, some of whom have been followed with measurements of blood pressure (BP) and body size (every 6-12 months) for as long as 15 years, providing us with important phenotypes of BP regulation. Subjects are young (mean age 20) and, with few exceptions, normotensive (many of them presumably pre-hypertensive). They are without age-related and hypertension-related confounding influences, and free of effects of antihypertensive drugs. We thus explore phenotype with early penetrance, those that may be less evident in older subjects with hypertension. A new interventional study conducted in the General Clinical Research Center - the Saline/Diuretic protocol - allows for the generation of phenotypes (renin and aldosterone levels and BP) in response to major shifts in Na balance. In a subset of subjects in Specific Aim 2., we also assess sensitivity of the BP to a small dose of thiazide diuretic to test the hypothesis that blacks have a more active thiazide-sensitive Na-Cl cotransporter than whites. Using single nucleotide polymorphisms in genes of Na-reabsorptive systems, we examine for linkage disequilibrium with the phenotypes. Additional family members will be recruited (parents and siblings) to extend association studies to the transmission disequilibrium test and to allow for the generation of haplotypes. In summary, by exploring candidate sites for increased Na retention in blacks in comparison to whites, we seek to identify new mechanisms for common forms of hypertension.