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: 7942840
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942840
• 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（由申请方提供）：高血压（HTN）是全球发病率和死亡率的主要原因，可导致心血管疾病、卒中和终末期肾病。HTN在任何个体中的常见形式的表现可能取决于各种遗传和环境因素，因此治疗这种容易诊断的疾病是一个重大挑战。最近，我们的实验室确定了一个新的HTN基因，STK 39，从一个基因组范围内的基线血压（BP）在旧秩序阿米什人，遗传同质的创始人人口。然后，我们在其他4个非阿米什白人人群中重复了这一发现（荟萃分析结合所有研究：N = 7，125，P < 10-6）。STK 39编码蛋白激酶，通常称为SPAK，其与WNK激酶和阳离子-氯共转运蛋白相互作用，作为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，我们已经确定了一个功能性变异，可能会影响BP增加STK 39的表达，从而改变肾钠排泄。来自我们小组和其他人的新证据表明，SPAK参与激活肾脏中噻嗪敏感性NaCl共转运的信号通路。因此，增加STK 39表达的基因型可能会改变肾盐处理和BP设定点，产生嗜钠表型，这可能适合用噻嗪类利尿剂校正。有趣的是，与高血压相关的STK 39基因型也与较低的空腹血糖相关，提高了STK 39基因型可能预测盐敏感性高血压患者亚组的可能性，噻嗪类利尿剂诱导的高血糖风险较低。我们假设STK 39基因型不仅与基线血压相关，而且与盐负荷和噻嗪类利尿剂的特异性一致反应相关。为了检验这些假设，我们计划招募120名阿米什人受试者，根据与基线BP较高和较低相关的基因型分为两组，每组60人，进行2项干预，专门测试肾脏氯化钠处理。干预措施是短期静脉内氯化钠负荷方案，随后是氢氯噻嗪（一种常用的噻嗪类利尿剂）的剂量依赖性药理学降压干预。这项工作将由一组年轻的研究者进行，他们具有遗传学、离子转运蛋白生理学、肾脏学、药代动力学/药效学和统计分析方面的专业知识。预计这些研究将阐明STK 39与其对肾氯化钠重吸收的可能功能作用之间的关系，从而鉴定盐敏感性高血压表型的重要介质。从这项工作中获得的见解最终可能有助于扩大我们对必需HTN的理解，使我们能够减少其遗传异质性，并通过鉴定利尿剂反应基因型将其管理转化为具有成本效益的个性化药物。 相关性：虽然高血压可以很容易地诊断，并有许多药物治疗，这种情况是管理不善，在许多患者和世界各地的发病率和死亡率的主要原因。由于新发现的高血压易感基因STK 39在肾钠转运中起着核心作用，我们提出了一项药物遗传学研究，以研究STK 39基因型与盐负荷和噻嗪类利尿剂氢氯噻嗪反应之间的关系。我们假设STK 39基因型将与两种干预措施的结果相关，并通过预测患者最有可能通过采用减盐饮食和服用噻嗪类利尿剂有效控制血压，从而有助于高血压的个性化护理。