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

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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.