GENOME WIDE META-ANALYSIS OF BLOOD PRESSURE RESPONSE TO B-BLOCKERS: RESULTS FROM INTERNATIONAL CONSORTIUM OF ANTIHYPERTENSIVE PHARMACOGENOMICS STUDIES.

Background-There exists a wide interindividual variability in blood pressure (BP) response to beta(1)-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants beta(1)-influencing blocker BP response. Methods and Results-Genome-wide association analysis for systolic BP and diastolic BP response to beta(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 beta(1)-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a beta(1)-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to beta(1)-blockers in the discovery meta-analysis (P=9.33x 10(-5), beta=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85x 10(-4), beta=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18 x 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. Conclusions-Data 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 beta(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.