학술논문
Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.
Document Type
article
Author
Armstrong, Nicole; Srinivasasainagendra, Vinodh; Ammous, Farah; Assimes, Themistocles; Beitelshees, Amber; Brody, Jennifer; Cade, Brian; Ida Chen, Yii-Der; Chen, Han; de Vries, Paul; Floyd, James; Franceschini, Nora; Guo, Xiuqing; Hellwege, Jacklyn; House, John; Hwu, Chii-Min; Kardia, Sharon; Lange, Ethan; Lange, Leslie; McDonough, Caitrin; Montasser, May; OConnell, Jeffrey; Shuey, Megan; Sun, Xiao; Tanner, Rikki; Wang, Zhe; Zhao, Wei; Carson, April; Edwards, Todd; Kelly, Tanika; Kenny, Eimear; Kooperberg, Charles; Loos, Ruth; Morrison, Alanna; Motsinger-Reif, Alison; Psaty, Bruce; Rao, Dabeeru; Redline, Susan; Rich, Stephen; Rotter, Jerome; Smith, Jennifer; Smith, Albert; Irvin, Marguerite; Arnett, Donna
Source
Subject
Language
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 Centers 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.