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

描述（由申请人提供）：高血压（HTN）是世界范围内发病率和死亡率的主要原因，导致心血管疾病、中风和终末期肾脏疾病。HTN的常见形式在任何个体中的表现可能取决于多种遗传和环境因素，因此治疗这种容易诊断的疾病是一项重大挑战。最近，我们的实验室发现了一种新的HTN基因，STK39，来自旧秩序阿米什人（一个遗传同质的创始人群体）基线血压（BP）的全基因组关联。然后，我们在另外4个非阿米什高加索人群中重复了这一发现（综合所有研究的荟萃分析：N = 7125, P < 10-6）。STK39编码一种通常被称为SPAK的蛋白激酶，它与WNK激酶和阳离子-氯共转运体相互作用，作为进化保守的信号通路的一部分，控制盐转运和渗透细胞体积调节。此外，我们还发现了一种可能通过增加STK39表达从而改变肾钠排泄来影响BP的功能变异。来自我们和其他人的新证据表明，SPAK参与激活肾中噻嗪敏感的NaCl共转运的信号通路。因此，增加STK39表达的基因型可能改变肾盐处理和血压设定值，产生嗜钠表型，可以用噻嗪类利尿剂纠正。有趣的是，与高血压相关的STK39基因型也与较低的空腹血糖相关，这提高了STK39基因型可能预测盐敏感高血压亚组发生噻嗪类利尿剂诱导的高血糖风险较低的可能性。我们假设感兴趣的STK39基因型不仅与基线血压有关，而且与盐负荷和噻嗪类利尿剂的特定一致反应有关。为了验证这些假设，我们计划招募120名阿米什受试者，根据与基线血压高低相关的基因型分为两组，每组60人，进行两项干预，专门测试肾脏氯化钠处理。干预措施是短期静脉注射氯化钠加载方案，然后使用氢氯噻嗪（一种常用的噻嗪类利尿剂）进行剂量依赖性药理学降压干预。这项工作将由一组具有遗传学、离子转运体生理学、肾脏病学、药代动力学/药效学和统计分析专业知识的年轻研究人员完成。预计这些研究将揭示STK39及其对肾脏氯化钠重吸收的可能功能影响之间的关系，从而确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可能最终有助于扩大我们对基本HTN的理解，使我们能够减少其遗传异质性，并通过确定利尿剂反应基因型将其管理转变为具有成本效益的个性化医疗。

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.