Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Marguerite R. Irvin, Colleen M. Sitlani, James S. Floyd, Bruce M. Psaty, Joshua C. Bis, Kerri L. Wiggins, Eric A. Whitsel, Til Sturmer, James Stewart, Laura Raffield, Fangui Sun, Ching Ti Liu, Hanfei Xu, Adrienne L. Cupples, Rikki M. Tanner, Peter Rossing, Albert Smith, Nuno R. Zilhão, Lenore J. Launer, Raymond NoordamJerome I. Rotter, Jie Yao, Xiaohui Li, Xiuqing Guo, Nita Limdi, Aishwarya Sundaresan, Leslie Lange, Adolfo Correa, David J. Stott, Ian Ford, J. Wouter Jukema, Vilmundur Gudnason, Dennis O. Mook-Kanamori, Stella Trompet, Walter Palmas, Helen R. Warren, Jacklyn N. Hellwege, Ayush Giri, Christopher O'Donnell, Adriana M. Hung, Todd L. Edwards, Tarunveer S. Ahluwalia, Donna K. Arnett, Christy L. Avery

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Original languageEnglish
Pages (from-to)1146-1153
Number of pages8
JournalAmerican Journal of Hypertension
Issue number12
StatePublished - Nov 15 2019

Bibliographical note

Publisher Copyright:
© 2019 American Journal of Hypertension, Ltd. All rights reserved.


  • blood pressure
  • genome-wide association study
  • hypertension
  • severe hypertension
  • treatment-resistant hypertension

ASJC Scopus subject areas

  • Internal Medicine


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