Genetics of CKD and Hypertension-Risk Prediction and Drug Response in the MVP

慢性肾脏病的遗传学与MVP的高血压风险预测和药物反应 慢性肾脏疾病(CKD)影响着全球8.5亿人。阻碍发展 CKD的发生和减缓其进展对于减少过早死亡和终末期肾脏病至关重要 疾病(ESRD)在这一不断增长的人口中。高危人群的风险预测和早期治疗 对于慢性肾脏病或合并慢性肾脏病对于减少肾脏疾病的并发症是最相关的。首先，我们 将生成加权遗传风险分数(GRS)，用于预测事件和 进展性CKD，并测试我们是否可以提高预测能力，超越常见的临床危险因素。我们的 产生GRS的主要方法将包括来自肾小球滤过率(GFR)的基因座 性状全基因组关联扫描(GWAS)(270名参与者，156个SNPs)和血压 (BP)达到全基因组意义的性状GWAS(781,119名参与者，498个SNPs)， 使我们能够评估这些特征对CKD严重程度的共同遗传贡献。基因 我们将包含在GRS中的信息比以前包含在CKD中的信息要广泛得多 研究，并应在添加到突发事件和进展性CKD风险时改进风险预测 方程式。作为第二种方法，我们将生成并测试多基因风险分数(PR) 评估包含更大一组变体的好处(不限于 在风险预测中的重要性)。2)第二，我们将扩大我们在抗击方面的工作 高血压(RH)是CKD和ESRD的潜在危险因素。在我们的RH GWA中 (17000例)9我们在肾上腺中确定了三个预测基因表达的基因座10 腺体[松弛蛋白(RXFP2)，纤维蛋白-2(FBN2)]或位于其突变具有 在产生醛固酮的腺瘤11，12中被发现。最近被确认 亚临床型原发性醛固酮增多症有多种表现， 它的患病率比以前认识到的要高得多，并可能先于未来的严重 高血压(HTN)和发病的CKD.4 13我们提议进行一系列药物基因组学研究 确定这些变异与特定的临床药物反应表型之间的关联 与原发性醛固酮增多症(轻度或亚临床形式)有关，包括由噻嗪引起的 低钾血症14，目的是及早发现和预防慢性肾脏病。3)最后，矿物质 CKD的代谢紊乱是CKD进展和心血管事件的重要预测因子。在这 目的：研究矿物质代谢标志物的遗传决定因素。此信息将 帮助我们在未来了解这些性状对CKD的共同遗传贡献。我们会 以以下具体目标完成我们的目标：目标1a)建立一系列加权的 GRSES/PR，以总结源自大规模GWA研究的标记的遗传效应 并测试他们预测突发事件和进展性CKD的能力。目标1b)：评估 加权GRS的加入提高了CKD临床风险预测模型的性能 适用于突发事件和进行性慢性肾脏病。目的2：评估候选基因之间的关联 (RXFP2、FBN2和CANAN1D)和事件使用者的钾反应 氢氯噻嗪(HCTZ)在治疗开始后15至180天。目标3：发现新事物 常见和罕见基因变异与血清甲状旁腺素、磷和钙的关系 在患有和不患有CKD的成年人中使用全基因组方法。目前的提案将 推广个性化医疗，为退伍军人事务部CKD患者或有CKD风险的患者提供护理。 我们已经组建了一个多学科小组，我们已经做好准备开展拟议的工作。

Genetics of CKD and Hypertension—Risk Prediction and Drug Response in the MVP Chronic kidney disease (CKD) affects 850 million people worldwide. Preventing the development of CKD and slowing its progression is critical to reducing premature death and end-stage renal disease (ESRD) in this growing population. Risk prediction and early treatment of people at risk for or with CKD is of upmost relevance to reduce the complications of kidney disease. First, we will generate weighted Genetic Risk Scores (GRS) for the prediction of incident and progressive CKD, and test if we can improve prediction beyond common clinical risk factors. Our primary approach to generating GRSes will include loci from the glomerular filtration rate (GFR) trait genome wide association scan (GWAS) (270 participants,156 SNPs), and Blood pressure (BP) trait GWAS (781,119 participants, 498 SNPs) that reached genome wide significance, allowing us to evaluate the shared genetic contribution of these traits to CKD severity. The genetic information we will include in the GRS is far more extensive than previously included in CKD studies, and should improve risk prediction when added to incident and progressive CKD risk equations. As a secondary approach, we will generate and test polygenic risk scores (PRS) to evaluate the benefit of including even a larger set of variants (not limited to the ones that reach GWAS significance) in risk prediction. 2) Second, we will extend our work in resistant hypertension (RH), a potent risk factor for the development of CKD and ESRD. In our RH GWAS (17000 cases) 9 we identified three loci with either predicted gene expression10 in the adrenal gland [relaxin (RXFP2), fibrillin-2 (FBN2)] or located in a gene (CACNA1D) whose mutations have been recognized in aldosterone producing adenomas11,12. It has been recently acknowledged that there is a broad spectrum of manifestations of subclinical primary hyperaldosteronism, whose prevalence is much greater than previously recognized13, and may precede future severe hypertension (HTN) and incident CKD.4 13 We propose a series of pharmacogenomic studies to identify the association between these variants and specific clinical drug response phenotypes related to primary hyperaldosteronism (mild or subclinical forms), including thiazide-induced hypokalemia14 with the goal of early detection and prevention of CKD. 3) Finally, mineral metabolism disorders of CKD are important predictors of CKD progression and CV events. In this aim, we will study the genetic determinants of mineral metabolism markers. This information will help us to understand in the future the share genetic contribution of these traits to CKD. We will accomplish our goals with the following specific aims: Aim 1a) To build a series of weighted GRSes/PRS to summarize the genetic effects of markers derived from large GWA studies from the MVP and test their ability to predict incident and progressive CKD. Aim 1b): To evaluate if the addition of the weighted GRS improves the performance of CKD clinical risk predicting models for incident and progressive CKD. Aim 2: To evaluate the association between candidate genes (RXFP2, FBN2, and CANAN1D) and the potassium response in incident users of hydrochlorothiazide (HCTZ) 15 to 180 days after therapy initiation. Aim 3: To discover new associations of common and rare genetic variants with serum PTH, phosphorus and calcium among adults with and without CKD using a genome wide approach. The current proposal will promote personalized medicine for the care provided to patients with or at risk of CKD in the VA. We have assembled a multidisciplinary team and we are well poised to conduct the work proposed.