Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension

J Am Heart Assoc. 2014 Nov 10;3(6):e001398. doi: 10.1161/JAHA.114.001398.


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(-3), odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics (P=7.69×10(-4), 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(-6), 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:; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).

Keywords: genetics; hypertension; pharmacology; resistant hypertension.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antihypertensive Agents / therapeutic use
  • Blood Pressure / drug effects
  • Blood Pressure / genetics*
  • Drug Resistance / genetics*
  • Drug Therapy, Combination
  • Female
  • Genetic Association Studies
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Hispanic or Latino / genetics
  • Humans
  • Hypertension / drug therapy
  • Hypertension / ethnology
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Odds Ratio
  • Phenotype
  • Plasma Membrane Calcium-Transporting ATPases / genetics*
  • Polymorphism, Single Nucleotide*
  • Puerto Rico / epidemiology
  • Risk Factors
  • United States / epidemiology
  • White People / genetics


  • ATP2B1 protein, human
  • Antihypertensive Agents
  • Genetic Markers
  • Plasma Membrane Calcium-Transporting ATPases

Associated data