Citations

Background There exists a wide interindividual variability in blood pressure ( BP ) response to β 1 ‐blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome‐wide meta‐analysis of genetic variants influencing β 1 ‐blocker BP response. Methods and Results Genome‐wide association analysis for systolic BP and diastolic BP response to β 1 ‐blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta‐analysis and single nucleotide polymorphisms (SNPs) with P <10 −4 were tested for replication in 2 independent randomized clinical trials of β 1 ‐blocker–treated patients of European ancestry (n=1552). Regions harboring the replicated SNP s were validated in a β 1 ‐blocker–treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST 1 was associated with systolic BP response to β 1 ‐blockers in the discovery meta‐analysis ( P =9.33×10 −5 , β=−3.21 mm Hg) and replicated at Bonferroni significance ( P =1.85×10 −4 , β=−4.86 mm Hg) in the replication meta‐analysis with combined meta‐analysis approaching genome‐wide significance ( P =2.18×10 −7 ). This SNP in BST 1 is in linkage disequilibrium with several SNP s with putative regulatory functions in nearby genes, including CD 38 , FBXL 5 , and FGFBP 1 , all of which have been implicated in BP regulation. SNP s in this genetic region were also associated with BP response in the black cohort. Conclusions Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST 1 containing locus on chromosome 4 is associated with β 1 ‐blocker BP response. Given the previous associations of this region with BP , this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

Abstract BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA &lt; 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P &lt; 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.