Статья

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

Vanessa FontanaDepartment of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, BrazilCaitrin W. McDonoughDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLYan GongDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLNihal M. El RoubyDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLAna Caroline C. SáDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLKent D. TaylorInstitute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute Harbor‐UCLA Medical Center, Torrance, CAY.‐D. Ida ChenInstitute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute Harbor‐UCLA Medical Center, Torrance, CAJohn G. GumsDepartment of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville, FLArlene B. ChapmanThe Renal Division, Department of Medicine, Emory University, Atlanta, GAStephen T. TurnerDivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MNCarl J. PepineDivision of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FLJulie A. JohnsonDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLRhonda M. Cooper‐DeHoffDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL

2014en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1161/jaha.114.001398

Цитирования и источники

Цитирований: 2Использованных источников: 0

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