WSO December 2023 – Issue 3 - 1248

1248
International Journal of Stroke 18(10)
Conclusion: We provide evidence for an association of genetic predisposition to higher BP with a higher risk of
3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive
drugs for improving functional outcomes in ischemic stroke.
Keywords
Ischemic stroke, antihypertensive drugs, blood pressure, Mendelian randomization
Received: 24 April 2023; accepted: 6 June 2023
Introduction
High blood pressure (BP) is commonly seen in ischemic
stroke patients.1-3 A genetic predisposition to higher BP has
been associated with an increased risk of any stroke, ischemic
stroke, and its main subtypes.4 Randomized controlled trials
(RCTs) found that BP-lowering treatment with anti-hypertensive
drugs, including angiotensin-converting enzyme inhibitor
(ACEI), angiotensin receptor blocker (ARB) and calcium
channel blocker (CCB), is beneficial in lowering stroke
risk.5,6 Pre-stroke use of antihypertensive drugs is also related
with better clinical outcomes.7 However, whether genetic predisposition
leads to less severe stroke or better clinical outcomes
after ischemic stroke onset remains unknown.
Mendelian randomization (MR) uses single nucleotide
polymorphisms (SNPs) as proxies for traits of risk factors
and is less prone to confounding bias and reverse causation
than observational studies.8 Of note, MR is commonly considered
valuable in exploring causality and predicting the
effect of interventions, which may explain possible intervention
targets in clinical practice including antihypertensive
treatment.9-11 Genome-wide association studies
(GWAS), with large samples and genetic data, further permit
the prediction of clinical outcomes of ischemic stroke,
especially in the absence of data from RCTs. Simultaneously,
the effects of drug action can be anticipated by the genetic
effects in the genes of their protein targets, as has previously
been applied to antihypertensive drugs.4
Herein, we employed MR to examine the effect of
genetically determined BP and its proxies for antihypertensive
drugs on clinical outcomes in ischemic stroke, with
data from the UK Biobank and International Consortium of
Blood Pressure of European ancestry.
Methods
Data availability
This study was conducted in accordance with the guidelines
for Strengthening the Reporting of Observational
Studies in Epidemiology-Mendelian randomization.12 We
used summary data from published studies for our analyses,
publicly available via the original studies. All studies
obtained relevant ethical approval and participant consent.
International Journal of Stroke, 18(10)
Exposure data
Genetic instruments for systolic BP (SBP), diastolic BP
(DBP), and pulse pressure (PP) were obtained from the
summary statistics of the GWAS meta-analysis consisting
of 757,601 individuals (458,577 from the UK Biobank and
299,024 from the International Consortium of Blood
Pressure) of European ancestry.13 In the pooled sample,
mean SBP and DBP were 138.4 (SD 21.5) and 82.8 (SD
11.4) mmHg, and the mean age of participants ranged from
56.8 to 62.1 years old. As genetic instruments for SBP and
DBP, we selected SNPs associated with SBP, DBP, and PP
at genome-wide significance level (p < 5 × 10−8) and
clumped for linkage disequilibrium (LD) to r2 < 0.001
based on the European 1000 Genomes panel.
Five commonly used antihypertensive drugs were
selected, including ACEI, ARB, CCB, beta-blocker (BB),
and thiazide diuretics, according to guidelines.14 Genetic
instruments for the effects of antihypertensive drugs were
obtained as the variants in the drug-targeted genes associated
with BP at a genome-wide significant level.4,15,16
Genes encoding the pharmacologic targets related to the
effect of common antihypertensive drugs on BP were identified
in DrugBank.17 After, the genomic regions and their
regulatory regions (promoters and enhancers) corresponding
to these genes were screened in Genecards.18 From all
the identified variants in each gene, only variants that were
significantly associated with SBP (p < 5 × 10−8) and
clumped to an LD threshold of r2 < 0.4 using the 1000G
European reference panel were considered as candidate
proxies for each medication class. This relatively lenient
LD threshold allows for an increased proportion of variance
explained and thus in statistical power.19,20 For additional
analysis, we also employed a more stringent LD
threshold (r2 < 0.1). There is only one genetic variant for
ACEI. To improve statistical capabilities, another method
was used to explore the construction of genetic instruments
to proxy ACEI: by obtaining genome-wide significant variants
in weak LD (r2 < 0.1) in or within ± 100 kb from angiotensin-converting
enzyme (ACE) that were associated
with serum ACE concentrations in a GWAS of 4, 174 participants
in the Outcome Reduction with Initial Glargine
Intervention study (resulting in 14 SNPs).21 These proxies
for ACEI have been validated in previous studies.16
WSO December 2023 – Issue 3

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