Pharmacogenetic GWAS meta-analysis of response to antihypertensive drugs
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2015-10-01
Date Acceptance
2015-01-01
Citation
Journal of Human Hypertension, 2015, 29 (10), pp.627-627
ISSN
0950-9240
Publisher
Nature Publishing Group
Start Page
627
End Page
627
Journal / Book Title
Journal of Human Hypertension
Volume
29
Issue
10
Copyright Statement
© 2015 The Authors.
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Grant Number
RDC02 79560
n/a
Subjects
Science & Technology
Life Sciences & Biomedicine
Peripheral Vascular Disease
Cardiovascular System & Cardiology
Publication Status
Published
Article Number
4B.02