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

MVP 中 CKD 和高血压风险预测和药物反应的遗传学

• 批准号: 10059136
• 负责人: Adriana Hung
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059136
• 关键词: Adrenal Glands; Adult; Affect; African American; Age; Albumins; Albuminuria; Aldosterone; Bicarbonates; Blood Pressure; Calcium; Candidate Disease Gene; Cardiovascular Diseases; Caring; Cessation of life; Chronic Kidney Failure; Clinical; Computerized Medical Record; Creatinine; DNA Repository; Data; Development; Diabetes Mellitus; Disease Progression; Early Diagnosis; Early Intervention; Early treatment; End stage renal failure; Equation; Event; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genetic study; Glomerular Filtration Rate; Goals; Healthcare; Hydrochlorothiazide; Hypertension; Individual; Kidney Diseases; Knowledge; Link; Meta-Analysis; Metabolic Diseases; Metabolism; Minerals; Mission; Mutation; Participant; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Phenotype; Phosphorus; Population; Potassium; Prevalence; Prevention; Primary Hyperaldosteronism; Publishing; RXFP2 gene; Relaxin; Resistant Hypertension; Risk; Risk Factors; Series; Serum; Serum Markers; Severities; Severity of illness; Stratification; Testing; Translating; Uric Acid; Variant; Veterans; Vitamin D; Work; base; blood pressure regulation; calcium phosphate; clinical predictors; clinical risk; cohort; disorder risk; fibrillin-2; genetic information; genetic variant; genome wide association study; genome-wide; improved; multidisciplinary; new therapeutic target; novel; personalized care; personalized medicine; polygenic risk score; precision medicine; predictive modeling; premature; prevent; programs; response; risk prediction; risk stratification; sex; thiazide; tool; trait; treatment response

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.

CKD和高血压的遗传学-MVP中的风险预测和药物反应 慢性肾脏病（CKD）影响着全球8.5亿人。防止发展 慢性肾脏病和减缓其进展是至关重要的，以减少过早死亡和终末期肾病 疾病（ESRD）在这个不断增长的人口。风险预测和高危人群的早期治疗 对于减少肾脏疾病的并发症具有最大的相关性。一是 将生成加权遗传风险评分（GRS），用于预测事件， 进展性慢性肾病，并测试我们是否可以改善常见临床风险因素以外的预测。我们 产生GRS的主要方法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SNP），和血压 (BP)性状GWAS（781，119名参与者，498个SNP）达到全基因组显著性， 使我们能够评估这些性状对CKD严重程度的共同遗传贡献。遗传 我们将在GRS中包含的信息比以前在CKD中包含的信息要广泛得多 研究，并应改善风险预测时，添加到事件和进展性CKD风险 方程作为第二种方法，我们将生成和测试多基因风险评分（PRS） 为了评估包括更大的变体集合（不限于达到以下的变体）的益处， GWAS显著性）在风险预测中的作用。2)第二，我们将扩大我们的工作， 高血压（RH）是CKD和ESRD发展的潜在风险因素。在我们的RH GWAS （17000例）9我们确定了肾上腺中预测基因表达的三个位点10， 腺体[松弛素（RXFP 2），松弛素-2（FBN 2）]或位于其突变具有以下特征的基因（CACNA 1D）中： 在醛固酮生成腺瘤中得到确认11，12。最近有人承认， 亚临床原发性醛固酮增多症有多种表现， 其患病率比以前认识到的要高得多13，并且可能在未来严重 高血压（HTN）和偶发性CKD。4 13我们提出了一系列药物基因组学研究， 确定这些变异体与特定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）相关，包括噻嗪诱导的 低钾血症14，目的是早期发现和预防CKD。3)最后，矿物 CKD代谢紊乱是CKD进展和CV事件的重要预测因子。在这 目的：研究矿物质代谢指标的遗传决定因素。这些信息将 帮助我们在未来了解这些性状对CKD的遗传贡献。我们将 实现我们的目标与以下具体目标：目标1a）建立一系列的加权 GRSes/PRS总结了来自大型GWA研究的标记的遗传效应， MVP并测试其预测偶发和进展性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 用于偶发和进行性CKD。目的2：评价候选基因之间的关联 （RXFP 2，FBN 2和CANAN 1D）和事件使用者的钾反应 氢氯噻嗪（HCTZ）治疗开始后15至180天。目标3：发现新的 常见和罕见遗传变异与血清甲状旁腺素、磷和钙的关系 使用全基因组方法在患有和不患有CKD的成人中进行。目前的提案将 促进为VA中CKD患者或有CKD风险的患者提供个性化医疗护理。 我们已经组建了一个多学科小组，我们已做好充分准备开展拟议的工作。