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

Vanessa Fontana, Caitrin W. McDonough, Yan Gong, Nihal M. El Rouby, Ana Caroline C Sá, Kent D. Taylor, Y. D. Ida Chen, John G. Gums, Arlene B. Chapman, Stephen T Turner, Carl J. Pepine, Julie A. Johnson, Rhonda M. Cooper-DeHoff

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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).

Original languageEnglish (US)
Article number001398
JournalJournal of the American Heart Association
Volume3
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Hypertension
Genes
Ischemia
trandolapril
Odds Ratio
Hispanic Americans
Single Nucleotide Polymorphism
Coronary Artery Disease
Blood Pressure
Verapamil
Pharmaceutical Preparations
Antihypertensive Agents
Myocardial Ischemia
Meta-Analysis
Body Mass Index
Logistic Models
Alleles
Genotype
Regression Analysis
Clinical Trials

Keywords

  • Genetics
  • Hypertension
  • Pharmacology
  • Resistant hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Fontana, V., McDonough, C. W., Gong, Y., El Rouby, N. M., Sá, A. C. C., Taylor, K. D., ... Cooper-DeHoff, R. M. (2014). Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension. Journal of the American Heart Association, 3(6), [001398]. https://doi.org/10.1161/JAHA.114.001398

Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension. / Fontana, Vanessa; McDonough, Caitrin W.; Gong, Yan; El Rouby, Nihal M.; Sá, Ana Caroline C; Taylor, Kent D.; Ida Chen, Y. D.; Gums, John G.; Chapman, Arlene B.; Turner, Stephen T; Pepine, Carl J.; Johnson, Julie A.; Cooper-DeHoff, Rhonda M.

In: Journal of the American Heart Association, Vol. 3, No. 6, 001398, 2014.

Research output: Contribution to journalArticle

Fontana, V, McDonough, CW, Gong, Y, El Rouby, NM, Sá, ACC, Taylor, KD, Ida Chen, YD, Gums, JG, Chapman, AB, Turner, ST, Pepine, CJ, Johnson, JA & Cooper-DeHoff, RM 2014, 'Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension', Journal of the American Heart Association, vol. 3, no. 6, 001398. https://doi.org/10.1161/JAHA.114.001398
Fontana, Vanessa ; McDonough, Caitrin W. ; Gong, Yan ; El Rouby, Nihal M. ; Sá, Ana Caroline C ; Taylor, Kent D. ; Ida Chen, Y. D. ; Gums, John G. ; Chapman, Arlene B. ; Turner, Stephen T ; Pepine, Carl J. ; Johnson, Julie A. ; Cooper-DeHoff, Rhonda M. / Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension. In: Journal of the American Heart Association. 2014 ; Vol. 3, No. 6.
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abstract = "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: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).",
keywords = "Genetics, Hypertension, Pharmacology, Resistant hypertension",
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T1 - Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension

AU - Fontana, Vanessa

AU - McDonough, Caitrin W.

AU - Gong, Yan

AU - El Rouby, Nihal M.

AU - Sá, Ana Caroline C

AU - Taylor, Kent D.

AU - Ida Chen, Y. D.

AU - Gums, John G.

AU - Chapman, Arlene B.

AU - Turner, Stephen T

AU - Pepine, Carl J.

AU - Johnson, Julie A.

AU - Cooper-DeHoff, Rhonda M.

PY - 2014

Y1 - 2014

N2 - 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: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).

AB - 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: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).

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KW - Pharmacology

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