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

Nicole D Armstrong¹, Vinodh Srinivasasainagendra², Farah Ammous^{3

4}, Themistocles L Assimes⁵, Amber L Beitelshees⁶, Jennifer Brody⁷, Brian E Cade⁸, Yii-Der Ida Chen⁹, Han Chen^{10

11}, Paul S de Vries¹⁰, James S Floyd^{12

13}, Nora Franceschini¹⁴, Xiuqing Guo⁹, Jacklyn N Hellwege^{15

16}, John S House¹⁷, Chii-Min Hwu¹⁸, Sharon L R Kardia³, Ethan M Lange¹⁹, Leslie A Lange¹⁹, Caitrin W McDonough²⁰, May E Montasser⁶, Jeffrey R O'Connell²¹, Megan M Shuey^{15

16}, Xiao Sun²², Rikki M Tanner¹, Zhe Wang²³, Wei Zhao^{3

4}, April P Carson²⁴, Todd L Edwards^{16

25}, Tanika N Kelly²⁶, Eimear E Kenny²⁷, Charles Kooperberg²⁸, Ruth J F Loos²³, Alanna C Morrison¹⁰, Alison Motsinger-Reif¹⁷, Bruce M Psaty^{7

12

13}, Dabeeru C Rao²⁹, Susan Redline⁸, Stephen S Rich³⁰, Jerome I Rotter⁹, Jennifer A Smith^{3

4}, Albert V Smith³¹, Marguerite R Irvin¹, Donna K Arnett³²

Affiliations

¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.
² Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States.
³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
⁴ Survey Research Center, Institute for Social Research, Ann Arbor, MI, United States.
⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, United States.
⁶ Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States.
⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States.
⁸ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.
¹⁰ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.
¹¹ Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.
¹² Department of Medicine, University of Washington, Seattle, WA, United States.
¹³ Department of Epidemiology, University of Washington, Seattle, WA, United States.
¹⁴ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States.
¹⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
¹⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States.
¹⁷ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, United States.
¹⁸ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
²⁰ Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States.
²¹ Department of Medicine, University of Maryland, Baltimore, MD, United States.
²² Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States.
²³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
²⁴ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
²⁵ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
²⁶ Division of Nephrology, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, United States.
²⁷ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
²⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
²⁹ Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States.
³⁰ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.
³¹ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, United States.
³² Office of the Provost, University of South Carolina, Columbia, SC, United States.

PMID: 38162683
PMCID: PMC10755672
DOI: 10.3389/fgene.2023.1278215

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

Nicole D Armstrong et al. Front Genet. 2023.

. 2023 Dec 13:14:1278215.

doi: 10.3389/fgene.2023.1278215. eCollection 2023.

Authors

Affiliations

¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.
² Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States.
³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
⁴ Survey Research Center, Institute for Social Research, Ann Arbor, MI, United States.
⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, United States.
⁶ Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States.
⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States.
⁸ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.
¹⁰ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.
¹¹ Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.
¹² Department of Medicine, University of Washington, Seattle, WA, United States.
¹³ Department of Epidemiology, University of Washington, Seattle, WA, United States.
¹⁴ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States.
¹⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
¹⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States.
¹⁷ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, United States.
¹⁸ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
²⁰ Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States.
²¹ Department of Medicine, University of Maryland, Baltimore, MD, United States.
²² Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States.
²³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
²⁴ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
²⁵ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
²⁶ Division of Nephrology, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, United States.
²⁷ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
²⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
²⁹ Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States.
³⁰ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.
³¹ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, United States.
³² Office of the Provost, University of South Carolina, Columbia, SC, United States.

PMID: 38162683
PMCID: PMC10755672
DOI: 10.3389/fgene.2023.1278215

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.

Keywords: TOPMed; antihypertensive response; blood pressure; treatment resistant hypertension; whole genome sequencing.

Copyright © 2023 Armstrong, Srinivasasainagendra, Ammous, Assimes, Beitelshees, Brody, Cade, Ida Chen, Chen, de Vries, Floyd, Franceschini, Guo, Hellwege, House, Hwu, Kardia, Lange, Lange, McDonough, Montasser, O’Connell, Shuey, Sun, Tanner, Wang, Zhao, Carson, Edwards, Kelly, Kenny, Kooperberg, Loos, Morrison, Motsinger-Reif, Psaty, Rao, Redline, Rich, Rotter, Smith, Smith, Irvin and Arnett.

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Conflict of interest statement

BP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson and Johnson. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources