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

Authors :
Nicole D. Armstrong
Vinodh Srinivasasainagendra
Farah Ammous
Themistocles L. Assimes
Amber L. Beitelshees
Jennifer Brody
Brian E. Cade
Yii-Der Ida Chen
Han Chen
Paul S. de Vries
James S. Floyd
Nora Franceschini
Xiuqing Guo
Jacklyn N. Hellwege
John S. House
Chii-Min Hwu
Sharon L. R. Kardia
Ethan M. Lange
Leslie A. Lange
Caitrin W. McDonough
May E. Montasser
Jeffrey R. O’Connell
Megan M. Shuey
Xiao Sun
Rikki M. Tanner
Zhe Wang
Wei Zhao
April P. Carson
Todd L. Edwards
Tanika N. Kelly
Eimear E. Kenny
Charles Kooperberg
Ruth J. F. Loos
Alanna C. Morrison
Alison Motsinger-Reif
Bruce M. Psaty
Dabeeru C. Rao
Susan Redline
Stephen S. Rich
Jerome I. Rotter
Jennifer A. Smith
Albert V. Smith
Marguerite R. Irvin
Donna K. Arnett
Source :
Frontiers in Genetics, Vol 14 (2023)
Publication Year :
2023
Publisher :
Frontiers Media S.A., 2023.

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.

Details

Language :
English
ISSN :
16648021
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.7b206fd782484f169fb7415ed4c3d533
Document Type :
article
Full Text :
https://doi.org/10.3389/fgene.2023.1278215