Frontiers in Genetics (Dec 2023)

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

  • Nicole D. Armstrong,
  • Vinodh Srinivasasainagendra,
  • Farah Ammous,
  • Farah Ammous,
  • Themistocles L. Assimes,
  • Amber L. Beitelshees,
  • Jennifer Brody,
  • Brian E. Cade,
  • Yii-Der Ida Chen,
  • Han Chen,
  • Han Chen,
  • Paul S. de Vries,
  • James S. Floyd,
  • James S. Floyd,
  • Nora Franceschini,
  • Xiuqing Guo,
  • Jacklyn N. Hellwege,
  • 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,
  • Megan M. Shuey,
  • Xiao Sun,
  • Rikki M. Tanner,
  • Zhe Wang,
  • Wei Zhao,
  • Wei Zhao,
  • April P. Carson,
  • Todd L. Edwards,
  • Todd L. Edwards,
  • Tanika N. Kelly,
  • Eimear E. Kenny,
  • Charles Kooperberg,
  • Ruth J. F. Loos,
  • Alanna C. Morrison,
  • Alison Motsinger-Reif,
  • Bruce M. Psaty,
  • Bruce M. Psaty,
  • Bruce M. Psaty,
  • Dabeeru C. Rao,
  • Susan Redline,
  • Stephen S. Rich,
  • Jerome I. Rotter,
  • Jennifer A. Smith,
  • Jennifer A. Smith,
  • Albert V. Smith,
  • Marguerite R. Irvin,
  • Donna K. Arnett

DOI
https://doi.org/10.3389/fgene.2023.1278215
Journal volume & issue
Vol. 14

Abstract

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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.

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