Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics (C.W.M., O.M., A.C.C.S., N.M.E.R., M.K.-S., M.S., J.G.G., R.M.C.-D., Y.G., J.A.J.), Department of Pharmaceutical Outcomes and Policy (C.D.), Department of Pharmaceutics, College of Pharmacy (A.N.D., R.S.P.S.), Genetics & Genomics Graduate Program, Genetics Institute (A.C.C.S., Y.S.), Department of Biology, College of Liberal Arts and Sciences (W.M.), Department of Community Health and Family Medicine, College of Medicine (J.G.G.), and Division of Cardiovascular Medicine, Department of Medicine (R.M.C.-D., J.A.J.), University of Florida, Gainesville; School of Pharmacy, College of Health Professions, Pacific University, Hillsboro, OR (M.K.-S.); Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (M.S.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Medicine (S.T.T.), Mayo Clinic, Rochester, MN; Human Genetics Center, Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); Section of Nephrology, Department of Medicine, University of Chicago, IL (A.B.C.); Department of Biomedical Informatics, Center for Pharmacogenomics (A.W.) and Department of Cancer Biology and Genetics, College of Medicine (W.S.), Ohio State University, Columbus; and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (S.E.S.).
Circ Genom Precis Med. 2018 Apr;11(4):e001854. doi: 10.1161/CIRCGEN.117.001854.
Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).
Our top SNP rs3784921 was in the gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; =2.09×10) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided =0.006). In addition, expression differed by rs3784921 genotype (=0.007), and rs1802409, a proxy SNP for rs3784921 (=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided =0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes and CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
血浆肾素是血压（BP）的重要调节因子。已表明血浆肾素活性（PRA）与降压药物对血压反应的变异性相关。我们进行了一项全基因组关联研究，使用来自 PEAR 研究（抗高血压反应的药物基因组学评估）的数据，鉴定与基线 PRA 相关的单核苷酸多态性（SNP）。
使用加性模型，对 461 名白人和 297 名黑人进行多元线性回归分析，调整年龄、性别和特定祖先的主要成分。通过测试阿替洛尔和氢氯噻嗪降压反应的预期关联方向，对顶级 SNP 进行优先排序。通过基因型的基因表达差异，使用 RNA 测序数据对 BP 反应优先级的顶级区域进行功能证据测试。通过在独立研究（PEAR-2）中对基线 PRA 进行功能评估，对具有功能证据的区域进行复制。
我们的顶级 SNP rs3784921 位于 基因区域。rs3784921 的 G 等位基因与较高的基线 PRA 相关（β=0.47；=2.09×10），并且对氢氯噻嗪的收缩压降低反应较小（β=2.97；单侧=0.006）。此外，rs3784921 基因型的 表达不同（=0.007），rs1802409，rs3784921 的替代 SNP（=0.98-1.00），在 PEAR-2 中复制（β=0.15；单侧=0.038）。通过 BP 反应信号优先排序与基线 PRA 相关的其他 SNP 位于/靠近基因 和 。
我们鉴定了多个与基线 PRA 相关的区域，这些区域通过 2 种机制不同的降压药物对 BP 反应进行了优先排序。
