The Relationship Between STK39, Salt Sensitivity, and HCTZ-induced BP Response

STK39、盐敏感性和 HCTZ 诱导的血压反应之间的关系

• 批准号: 7742809
• 负责人: YEN PEI CHRISTY CHANG
• 金额: $ 31.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742809
• 关键词: Adopted; Adverse effects; Alleles; Amish; Benefits and Risks; Blood Pressure; Bypass; Cardiovascular Diseases; Caring; Cations; Caucasians; Caucasoid Race; Cell Volumes; Chloride Ion; Chlorides; Clinical; Clinical Research; Complex; Development; Diagnosis; Disease; Diuretics; Dose; Drug Combinations; Drug Kinetics; End stage renal failure; Environment; Equilibrium; Essential Hypertension; Excretory function; Family; Founder Generation; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genotype; Glucose; Goals; Hour; Hydrochlorothiazide; Hyperglycemia; Hypertension; Hypotension; Individual; Intervention; Intravenous; Intravenous infusion procedures; Ions; Kidney; Knowledge; Laboratories; Life; Light; Maryland; Mediator of activation protein; Medicine; Meta-Analysis; Molecular Genetics; Morbidity - disease rate; Nephrology; Newly Diagnosed; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Phenotype; Phosphotransferases; Physiology; Plasma; Play; Population; Process; Protein Kinase; Proteins; Protocols documentation; Recruitment Activity; Reducing diet; Regulation; Renal function; Research Personnel; Risk; Role; Saline; Signal Pathway; Sodium; Sodium Chloride; Stroke; Subgroup; Susceptibility Gene; Testing; Thiazide Diuretics; United States; Universities; Variant; Work; base; blood pressure regulation; cost; design; dosage; fasting glucose; genome wide association study; high risk; hypertension treatment; insight; interest; knowledge translation; medical schools; mortality; multidisciplinary; normotensive; novel; response; salt sensitive; symporter; thiazide; trait

DESCRIPTION (provided by applicant): Hypertension (HTN) is a leading cause of morbidity and mortality worldwide, contributing to cardiovascular disease, stroke, and end stage kidney disease. Manifestation of the common form of HTN in any one individual is likely dependent on a variety of genetic and environment factors, hence treatment of this easily diagnosed condition is a major challenge. Recently, our laboratory identified a novel HTN gene, STK39, from a genome-wide association of baseline blood pressure (BP) in the Old Order Amish, a genetically homogeneous founder population. We then replicated this finding in 4 other non-Amish Caucasian populations (meta-analysis combining all studies: N = 7,125, P < 10-6). STK39 encodes a protein kinase more commonly known as SPAK, which interacts with WNK kinases and cation-chloride co-transporters as a part of an evolutionarily conserved signaling pathway that controls salt transport and osmotic cell volume regulation. In addition we have identified a functional variant that may influence BP by increasing STK39 expression and consequently altering renal sodium excretion. An emerging body of evidence from our group and others demonstrates that SPAK participates in a signaling pathway that activates thiazide-sensitive NaCl cotransport in the kidney. Thus, genotypes that increase STK39 expression might alter renal salt handling and the BP set point, generating a sodium avid phenotype that may be amenable to correction with thiazide diuretics. Interestingly, the STK39 genotypes associated with higher BP are also associated with lower fasting glucose, raising the possibility that STK39 genotypes might predict a subgroup of salt-sensitive hypertensives with lower risk for thiazide diuretic-induced hyperglycemia. We hypothesize that the STK39 genotypes of interest are not only associated with baseline BP, but also with specific concordant responses to salt loading and thiazide diuretics. To test these hypotheses, we plan to recruit 120 Amish subjects, divided into two groups of 60 based on genotypes associated with higher versus lower baseline BP to perform 2 interventions that specifically test renal sodium chloride handling. The interventions are a short-term intravenous NaCl loading protocol followed by a dose-dependent pharmacologic BP lowering intervention with hydrochlorothiazide, a commonly prescribed thiazide diuretic. This work will be performed by a team of young investigators with expertise in genetics, ion-transporter physiology, nephrology, pharmacokinetics/pharmacodynamics, and statistical analysis. It is anticipated that these studies will shed light on the relationship between STK39 and its likely functional effect on renal sodium chloride reabsorption, thus identifying an important mediator of the salt sensitive hypertensive phenotype. The insight gained from this work may eventually help to expand our understanding of essential HTN, allowing us to reduce its genetic heterogeneity and convert its management into cost-effective personalized medicine through the identification of diuretic-responsive genotypes. RELEVANCE: Although hypertension can be easily diagnosed and there are many pharmacologic treatments, this condition is poorly managed in many patients and a leading cause of morbidity and mortality worldwide. Because a newly identified hypertension susceptibility gene, STK39, plays a central role in renal sodium transport, we propose a pharmacogenetics study to examine the relationships between STK39 genotypes and responses to salt loading and to thiazide diuretics, hydrochlorothiazide. We hypothesize that STK39 genotypes will be associated with the outcome of both interventions and can contribute to personalized care for hypertension by predicting patients most likely to effectively control their blood pressure by adopting salt-reducing diet and taking thiazide diuretics.

描述（由申请人提供）：高血压（HTN）是全球发病率和死亡率的主要原因，导致心血管疾病，中风和末期肾脏疾病。 HTN在任何一个人中的共同形式的表现都可能取决于各种遗传和环境因素，因此对这种易于诊断的状况进行治疗是一个主要挑战。最近，我们的实验室确定了一种新型的HTN基因STK39，它是从基线血压（BP）的旧顺序阿米什（Amish）的基因组均值（BP）中的，这是一个遗传均质的创始人人群。然后，我们在其他4个非亚美高加索人群中复制了这一发现（结合所有研究的荟萃分析：n = 7,125，p <10-6）。 STK39编码更常见的SPAK的蛋白激酶，该蛋白激酶与WNK激酶和阳离子 - 氯化物的共转运蛋白相互作用，这是控制盐转运和渗透细胞体积调节的进化保守信号通路的一部分。此外，我们已经确定了一种功能变体，该功能变体可能通过增加STK39表达并因此改变肾脏钠排泄而影响BP。来自我们小组和其他人的新兴证据表明，SPAK参与了激活肾脏中对噻嗪类敏感的NaCl共晶的信号传导途径。因此，增加STK39表达的基因型可能会改变肾脏盐的处理和BP设定点，从而产生一种可能可以通过噻嗪类利尿剂校正的钠avid表型。有趣的是，与较高BP相关的STK39基因型也与较低的空腹葡萄糖有关，从而增加了STK39基因型可能预测盐敏感性高敏敏感性的亚组，其硫氮化性利尿剂诱导高血糖的风险较低。我们假设感兴趣的STK39基因型不仅与基线BP有关，而且还与对盐负荷和噻嗪类利尿剂的特定一致反应有关。为了检验这些假设，我们计划招募120名AMISH受试者，分为两组60组，基于与较高基线BP相关的基因型，以执行2种干预措施，这些干预措施专门测试肾氯化钠处理。干预措施是一种短期静脉注射NaCl加载方案，然后是剂量依赖的药理学BP降低干预措施，氢氯噻嗪是一种通常处方的硫嗪利尿剂。这项工作将由一个年轻研究人员组成的团队，具有遗传学，离子转运蛋白生理学，肾脏病，药代动力学/药物学和统计分析方面的专业知识。可以预料，这些研究将阐明STK39及其可能对肾氯化钠的功能作用之间的关系，从而确定了盐敏感的高血压表型的重要介体。从这项工作中获得的洞察力最终可能有助于扩大我们对基本HTN的理解，使我们能够通过鉴定利尿反应性基因型来减少其遗传异质性，并将其管理转化为具有成本效益的个性化医学。 相关性：尽管高血压很容易被诊断出来，并且有许多药理学治疗，但是在许多患者中，这种病情管理不良，并且是全球发病率和死亡率的主要原因。由于新鉴定的高血压易感基因STK39在肾脏钠转运中起着核心作用，因此我们提出了一项药物遗传学研究，以研究STK39基因型与对盐负荷和对硫代硫代利尿剂的反应之间的关系。我们假设STK39基因型将与两种干预措施的结果有关，并可以通过预测最有可能通过采用降盐饮食并服用硫嗪利尿剂来有效控制其血压的患者，从而为高血压提供个性化护理。