Dataset Information

Genome-Wide Meta-Analysis of Blood Pressure Response to ?1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

ABSTRACT: BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to ?1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing ?1-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to ?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 ?1-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a ?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 ?1-blockers in the discovery meta-analysis (P=9.33×10-5, ?=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10-4, ?=-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 ?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.

SUBMITTER: Singh S

PROVIDER: S-EPMC6759913 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

Singh Sonal S Warren Helen R HR Hiltunen Timo P TP McDonough Caitrin W CW El Rouby Nihal N Salvi Erika E Wang Zhiying Z Garofalidou Tatiana T Fyhrquist Frej F Kontula Kimmo K KK Glorioso Valeria V Zaninello Roberta R Glorioso Nicola N Pepine Carl J CJ Munroe Patricia B PB Turner Stephan T ST Chapman Arlene B AB Boerwinkle Eric E Johnson Julie A JA Gong Yan Y Cooper-DeHoff Rhonda M RM

Journal of the American Heart Association 20190819 16

BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to β1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β1-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to β1-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of ...[more]

PMID: 31423876

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Project description:We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10-8 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10-4 , Beta = 3.09, diastolic BP response P = 5 × 10-3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients' subgroup (P = 2.35 × 10-4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

Project description:Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ? 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

Dataset Information

Genome-Wide Meta-Analysis of Blood Pressure Response to ?1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

Publications

Genome-Wide Meta-Analysis of Blood Pressure Response to β<sub>1</sub>-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

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