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. 

TITLE=Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1278215

DOI=10.3389/fgene.2023.1278215

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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 (<italic>n</italic> = 1,705). A normotensive control group was defined as individuals with BP &lt; 140/90 mmHg (<italic>n</italic> = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP &lt; 140/ 90 mmHg (<italic>n</italic> = 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).</p><p><bold>Results:</bold> One variant in the known HTN locus, <italic>KCNK3</italic>, was a top finding in the multi-ethnic analysis (<italic>p</italic> = 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 <italic>AGTPBP, MYL4, PDCD4, BBS9, ERG,</italic> and <italic>IER3</italic>.</p><p><bold>Discussion:</bold> Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.</p>