大规模以基因为中心的分析确定了耐药性高血压的多态性。
Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension.
作者信息
Fontana Vanessa, McDonough Caitrin W, Gong Yan, El Rouby Nihal M, Sá Ana Caroline C, Taylor Kent D, Chen Y-D Ida, Gums John G, Chapman Arlene B, Turner Stephen T, Pepine Carl J, Johnson Julie A, Cooper-DeHoff Rhonda M
机构信息
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil (V.F.).
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL (C.W.M.D., Y.G., N.M.E.R., A.C.C., J.G.G., J.A.J., R.M.C.D.H.).
出版信息
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
www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).
背景
顽固性高血压（RHTN）是指尽管使用了至少3种抗高血压药物但血压（BP）仍未得到控制，与血压得到控制的高血压相比，其心血管风险更高。然而，关于与RHTN相关的基因变异的数据很少。
方法和结果
我们使用了一个包含约50000个单核苷酸多态性（SNP）的以基因为中心的阵列，来识别来自INVEST-GENES（国际维拉帕米缓释片-群多普利研究-基因亚研究）的患有冠状动脉疾病（CAD）的高血压参与者中与RHTN相关的多态性。RHTN被定义为使用3种药物时血压≥140/90，或使用4种或更多药物时的任何血压值。在欧洲裔美国人（n = 904）和西班牙裔（n = 837）中进行逻辑回归分析，使用针对年龄、性别、随机治疗分配、体重指数、祖先主成分以及RHTN的其他重要预测因素进行调整的加性模型。在来自WISE（女性缺血综合征评估）的241名欧洲裔美国女性中对顶级SNP进行重复验证，其中RHTN的定义类似。为了研究rs12817819的功能作用，在全血中测量mRNA表达。我们发现ATP2B1 rs12817819在INVEST欧洲裔美国人（P值 = 2.44×10⁻³，优势比 = 1.57 [1.17至2.01]）和INVEST西班牙裔（P = 7.69×10⁻⁴，优势比 = 1.76 [1.27至2.44]）中均与RHTN相关。在WISE中rs12817819观察到一致的趋势，并且INVEST-WISE荟萃分析结果达到全芯片显著性（P = 1.60×10⁻⁶，优势比 = 1.65 [1.36至1.95]）。表达分析揭示了rs12817819基因型在ATP2B1表达上的显著差异。
结论
在有记录的CAD或疑似缺血性心脏病的高血压参与者中，ATP2B1 rs12817819 A等位基因与RHTN风险增加相关。
临床试验注册网址
www.clinicaltrials.gov；唯一标识符：NCT00133692（INVEST），NCT00000554（WISE）。
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