4B.02. Pharmacogenetic GWAS meta-analysis of response to antihypertensive drugs

Background: Antihypertensive drugs are widely prescribed to lower blood pressure (BP), however there is significant inter-individual variation in treatment response, which may be due to genetic variation. By identifying genetic variants associated with a differential treatment response, it is hoped...

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Bibliographic Details
Published in:Journal of human hypertension 2015-10, Vol.29 (10), p.627
Main Authors: Warren, Helen, Sever, Peter, Poulter, Neil, Stanton, Alice, Caulfield, Mark, Munroe, Patricia
Format: Article
Language:English
Subjects:
Analysis
Antihypertensive agents
Drug therapy
Genetic aspects
Health aspects
Hypertension
Pharmacogenomics
Single nucleotide polymorphisms
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Summary:Background: Antihypertensive drugs are widely prescribed to lower blood pressure (BP), however there is significant inter-individual variation in treatment response, which may be due to genetic variation. By identifying genetic variants associated with a differential treatment response, it is hoped that pharmacogenetics may aid in the selection of optimal treatments. So far, only three genetic loci have been validated from pharmacogenetic genomewide association studies (GWAS), only for BP response to diuretics. It has been hypothesised that the loci associated with BP would also modify the effects of response to antihypertensives, however no significant pharmacogenetic associations have been found. Methods: We have derived novel methods to take advantage of data from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), where hypertensive patients were randomized to either a betablocker (BB) or a calcium-channel-blocker (CCB). A pharmacogenetic GWAS has been performed using genetic data for 3,804 Europeans from UK/Ireland and 2,468 from Scandinavia, followed by a combined meta-analysis. Subjects were restricted to those on monotherapy treatment, comparing BB vs CCB patients within a linear regression drug-gene interaction analysis for three BP-related phenotypes: systolic BP (SBP), diastolic BP (DBP) and heart rate (HR). The response was defined as the mean phenotype measure over all longitudinal visits whilst on monotherapy, and adjusted for several covariates, including baseline BP, to eliminate any confounding effects. Any subjects taking BB (or CCB) drugs at baseline were excluded, resulting in a total sample size of up to 1,659 UK and 961 Scandinavian subjects. Results: We have identified one novel genetic locus on chromosome 11, reaching genome-wide significance for HR response. Furthermore we performed an updated look-up for 79 SNPs published for BP and identified two variants with significant pharmacogenetic association after Bonferroni correction: another for HR response on chromosome 11, and one for SBP response on chromosome 4, each of which has potential relevance and functional support. This data is now contributing to a large scale GWAS meta-analysis for antihypertensive response, which we are leading within an international pharmacogenetics consortium, adapted to combine data from clinical trials and observational studies. doi: 10.1038/jhh.2015.90
ISSN:0950-9240
DOI:10.1038/jhh.2015.90