RESUMO
BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to ß1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing ß1-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to ß1-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 ß1-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a ß1-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to ß1-blockers in the discovery meta-analysis (P=9.33×10-5, ß=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10-4, ß=-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 BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with ß1-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.