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Author Notes:

Correspondence to: Rhonda M. Cooper-DeHoff, PharmD, MS, Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine, Colleges of Pharmacy and Medicine, Center for Pharmacogenomics, University of Florida, P.O. Box 100486, Gainesville, FL. E-mail: dehoff@cop.ufl.edu

We thank the INVEST site investigators and the INVEST‐GENES participants.

We acknowledge and thank the valuable contributions of the PEAR study participants, support staff, and study physicians.

Gong, Gums, Chapman, Turner, Pepine, Johnson, and Cooper‐DeHoff received funding from the National Institutes of Health.

The other authors report no conflicts.


Research Funding:

This project was supported by NIH grants R01HL074730, and U01‐GM074492, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. INVEST was supported by the University of Florida and grants from BASF Pharma and Abbott Laboratories.

PEAR was supported by the National Institutes of Health Pharmacogenomics Research Network grant U01‐GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); UL1 TR000135 (Mayo Clinic) and funds from the Mayo Foundation.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Cardiovascular System & Cardiology
  • genetics
  • hypertension
  • pharmacology
  • resistant hypertension

Large-Scale Gene-Centric Analysis Identifies Polymorphisms for Resistant Hypertension

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Journal Title:

Journal of the American Heart Association


Volume 3, Number 6


, Pages e001398-e001398

Type of Work:

Article | Final Publisher PDF


Background: Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN. Methods and Results: We used a gene-centric array containing ≈50 000 single-nucleotide polymorphisms (SNPs) to identify polymorphisms associated with RHTN in hypertensive participants with coronary artery disease (CAD) from INVEST-GENES (the INnternational VErapamil-SR Trandolapril STudy-GENEtic Substudy). RHTN was defined as BP≥140/90 on 3 drugs, or any BP on 4 or more drugs. Logistic regression analysis was performed in European Americans (n=904) and Hispanics (n=837), using an additive model adjusted for age, gender, randomized treatment assignment, body mass index, principal components for ancestry, and other significant predictors of RHTN. Replication of the top SNP was conducted in 241 European American women from WISE (Women's Ischemia Syndrome Evaluation), where RHTN was defined similarly. To investigate the functional effect of rs12817819, mRNA expression was measured in whole blood. We found ATP2B1 rs12817819 associated with RHTN in both INVEST European Americans (P-value=2.44 × 10<sup>-3</sup>, odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics (P=7.69 × 10<sup>-4</sup>, odds ratio=1.76 [1.27 to 2.44]). A consistent trend was observed at rs12817819 in WISE, and the INVEST-WISE meta-analysis result reached chip-wide significance (P=1.60 × 10<sup>-6</sup>, odds ratio=1.65 [1.36 to 1.95]). Expression analyses revealed significant differences in ATP2B1 expression by rs12817819 genotype. Conclusions: The ATP2B1 rs12817819 A allele is associated with increased risk for RHTN in hypertensive participants with documented CAD or suspected ischemic heart disease. Clinical Trial Registration: URL: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).

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© 2014 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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