Author:
Armstrong Nicole D.,Srinivasasainagendra Vinodh,Ammous Farah,Assimes Themistocles L.,Beitelshees Amber L.,Brody Jennifer,Cade Brian E.,Ida Chen Yii-Der,Chen Han,de Vries Paul S.,Floyd James S.,Franceschini Nora,Guo Xiuqing,Hellwege Jacklyn N.,House John S.,Hwu Chii-Min,Kardia Sharon L. R.,Lange Ethan M.,Lange Leslie A.,McDonough Caitrin W.,Montasser May E.,O’Connell Jeffrey R.,Shuey Megan M.,Sun Xiao,Tanner Rikki M.,Wang Zhe,Zhao Wei,Carson April P.,Edwards Todd L.,Kelly Tanika N.,Kenny Eimear E.,Kooperberg Charles,Loos Ruth J. F.,Morrison Alanna C.,Motsinger-Reif Alison,Psaty Bruce M.,Rao Dabeeru C.,Redline Susan,Rich Stephen S.,Rotter Jerome I.,Smith Jennifer A.,Smith Albert V.,Irvin Marguerite R.,Arnett Donna K.
Abstract
Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data.Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American).Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74–0.88)]. This variant was replicated in the Vanderbilt University Medical Center’s DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3.Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.
Subject
Genetics (clinical),Genetics,Molecular Medicine