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Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

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Objective We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH). Results Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH. Conclusions This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
ARTICLE OPEN ACCESS
Genetically determined blood pressure,
antihypertensive drug classes, and risk of
stroke subtypes
Marios K. Georgakis, MD, PhD,* Dipender Gill, MD, PhD,* Alastair J.S. Webb, DPhil, Evangelos Evangelou, PhD,
Paul Elliott, PhD, Cathie L.M. Sudlow, DPhil, Abbas Dehghan, MD, PhD, Rainer Malik, PhD,
Ioanna Tzoulaki, PhD,and Martin Dichgans, MD
Neurology®2020;95:1-e9. doi:10.1212/WNL.0000000000009814
Correspondence
Dr. Dichgans
martin.dichgans@
med.uni-muenchen.de
Abstract
Objective
We employed Mendelian randomization to explore whether the eects of blood pressure (BP)
and BP-lowering through dierent antihypertensive drug classes on stroke risk vary by stroke
etiology.
Methods
We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants
in genes encoding antihypertensive drug targets from genome-wide association studies
(GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined
associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes
(large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and
lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).
Results
Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any
stroke, ischemic stroke, and ICH. We found associations between genetically determined BP
and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke
compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic
proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any
stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong
associations with small vessel stroke and the related radiologic phenotype of WMH.
Conclusions
This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH.
We nd dierences in the eects of BP and BP-lowering through antihypertensive drug classes
between stroke subtypes and identify calcium channel blockade as a promising strategy for
preventing manifestations of cerebral small vessel disease.
*These authors contributed equally to this work as cofirst authors.
These authors contributed equally to this work as colast authors.
From the Institute for Stroke and Dementia Res earch (ISD), University Hospital (M. K.G., R.M., M.D.), and Graduate School for Sy stemic Neurosciences (M.K.G.), Ludwig-Max imilians-
Universit¨
at LMU, Munich, Germany; Department of Biosta tistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T. ), UK Dementia Research Institute (P.E., A.D.),
Health Data Research-UK London (P. E.), and MRC-PHE Centre for Environment, School of Publ ic Health (I.T.), Imperial College London; Centre for Pr evention of Stroke and Dementia,
Department of Clinical Neurosciences (A.J.S.W .), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), Uni versity of Ioannina Medical School, Greece; National
Institute for Health Research Imperia l College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Ed inburgh, UK; Munich
Cluster for Systems Neurology (SyNergy) (M. D.); and German Centre for Neurodegenerative Diseas es (DZNE) (M.D.), Munich, Germany.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
The Article Processing Charge was funded by Imperial College London.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1
Published Ahead of Print on July 1, 2020 as 10.1212/WNL.0000000000009814
Stroke ranks among the leading causes of death and disability
worldwide.
1,2
High blood pressure (BP) is the major risk
factor for both ischemic and hemorrhagic stroke, accounting
for ;50% of the population attributable risk worldwide.
36
BP lowering reduces stroke risk with known dierences be-
tween antihypertensive drug classes.
7,8
Randomized con-
trolled trials (RCTs) found calcium channel blockers (CCBs)
to be superior to other drug classes, and specically β-blockers
(BB), in lowering stroke risk.
7,9,10
However, it remains un-
known whether the eects of BP or BP lowering through
specic drug classes vary between stroke etiologies. In light of
largely variable mechanisms between large artery stroke
(LAS), cardioembolic stroke (CES), small vessel stroke
(SVS), and deep and lobar intracerebral hemorrhage
(ICH),
11,12
dierences seem possible and might have rele-
vance for therapeutic decisions.
Mendelian randomization uses genetic variants as proxies
for traits of interest and is by design less prone to con-
founding and reverse causation than observational stud-
ies.
13
As such, Mendelian randomization has been proven
valuable in exploring causality and in predicting the eects
of interventions,
1317
as we recently showed for the eects
of antihypertensive drugs on vascular outcomes.
18
The
large samples in genome-wide association studies (GWAS)
further permit exploration of outcomes for which there are
no adequate data from RCTs, as is the case for BP-lowering
and stroke subtypes. Here, leveraging genetic data on BP
19
and stroke,
20
we employed Mendelian randomization to
examine the eects of genetically determined BP and ge-
netic proxies for antihypertensive drug classes on stroke
subtypes, as well as on white matter hyperintensities
(WMH), a radiologic manifestation of small vessel dis-
ease (SVD).
Methods
Standard protocol approvals, registrations,
and patient consents
This study was conducted in accordance with the guidelines
for Strengthening the Reporting of Observational Studies in
EpidemiologyMendelian randomization (STROBE-MR).
21
All data were derived from studies that had already obtained
ethical review board approvals.
Genetic instrument selection
Data sources are detailed in table 1. We used summary sta-
tistics from the discovery GWAS meta-analysis of the In-
ternational Consortium for Blood Pressure (ICBP) and the
UK Biobank (UKB), based on 757,601 individuals of Euro-
pean ancestry.
19
In the pooled sample, mean systolic BP
(SBP) and diastolic BP (DBP) were 138.4 (SD 21.5) and 82.8
(SD 11.4) mm Hg, respectively. As genetic instruments for
SBP and DBP, we selected single nucleotide polymorphisms
(SNPs) associated with SBP or DBP at genome-wide signif-
icance level (p<5×10
8
) and clumped for linkage disequi-
librium (LD) to r
2
< 0.001 based on the European 1,000
Genomes panel. We estimated the proportion of variance in
SBP and DBP explained by each instrument
22
and calculated
F statistics to measure instrument strength (tables e-1 and e-2,
doi.org/10.5061/dryad.dfn2z34wj).
23
We further selected genetic variants as proxies for the SBP-
lowering eects of common antihypertensive drug classes
(gure 1). According to our previously described strategy,
18
we identied the genes encoding pharmacologic targets re-
lated to BP-lowering for common antihypertensive drug
classes in DrugBank
24
and screened the genomic regions
corresponding to these genes and their regulatory regions
(promoters and enhancers).
25
For the main analyses, we se-
lected SNPs associated with SBP at genome-wide signicance
(p<5×10
8
) that were at moderate to low LD (r
2
< 0.4)
according to previously described approaches,
2628
with
sensitivity analyses using a more stringent LD threshold (r
2
<
0.1) (table e-3, doi.org/10.5061/dryad.dfn2z34wj). The
genes and the specic genomic regions screened for identi-
cation of genetic proxies for each antihypertensive drug class
are detailed in table e-4 (doi.org/10.5061/dryad.dfn2z34wj).
Primary outcomes and etiologically
related phenotypes
The primary outcomes for our analyses were any stroke, is-
chemic stroke and its Trial of Org 10172 in Acute Stroke
Treatment (TOAST)dened subtypes (LAS, CES, SVS),
29
or ICH and its location-specic subtypes, i.e. lobar (origi-
nating at cerebral cortex or corticalsubcortical junction) and
deep (originating at thalamus, internal capsule, basal ganglia,
deep periventricular white matter, cerebellum, or brain-
stem).
30
Genetic association estimates for any stroke, ische-
mic stroke, and its subtypes were obtained from the
Glossary
ACE = angiotensin-converting enzyme; BB =β-blockers; BP = blood pressure; CCB = calcium channel blocker; CES =
cardioembolic stroke; DBP = diastolic blood pressure; GWAS = genome-wide association studies; ICBP = International
Consortium for Blood Pressure; ICH = intracerebral hemorrhage; ISGC = International Stroke Genetics Consortium; IVW =
inverse variance weight; LAS = large artery stroke; LD = linkage disequilibrium; MR-PRESSO = Mendelian randomization
pleiotropy residual sum and outlier; OR = odds ratio; RCT = randomized controlled trial; SBP = systolic blood pressure; SNP =
single nucleotide polymorphism; SVD = small vessel disease; SVS = small vessel stroke; UKB = UK Biobank; WMH = white
matter hyperintensity.
2Neurology | Volume 95, Number 4 | July 28, 2020 Neurology.org/N
MEGASTROKE multiethnic GWAS meta-analysis of 67,162
cases (60,341 ischemic stroke, 6,688 LAS, 9,006 CES, 11,710
SVS) and 454,450 controls.
20,31
For ICH, we used the sum-
mary statistics from the International Stroke Genetics Con-
sortium (ISGC) meta-analysis by Woo et al.
30
including 1,545
cases (664 lobar, 881 deep) and 1,481 controls. In addition,
we performed Mendelian randomization analyses for the ra-
diologic phenotype of WMH volume, a manifestation of ce-
rebral SVD etiologically related to SVS and ICH. We
performed a GWAS analysis for total volume of WMH, de-
rived from T1 and T2 uid-attenuated inversion recovery
images in the UKB data following a previously described
approach,
32
as detailed in e-Methods (doi.org/10.5061/
dryad.dfn2z34wj).
Statistical analysis
For SBP and DBP, we calculated individual Mendelian ran-
domization estimates and standard errors from the SNP
exposure and SNPoutcome associations using the Wald es-
timator and the Delta method; second-order weights were
used.
33
The Mendelian randomization associations for SBP
and DBP with the primary outcomes were estimated by
pooling individual Mendelian randomization estimates using
xed-eects inverse variance weighted (IVW) meta-analy-
ses.
33
All Mendelian randomization associations between
SBP, DBP, and stroke were scaled to 10 mm Hg increment in
SBP and 5 mm Hg in DBP.
For the antihypertensive drug classes, including instruments
at moderate to low LD (r
2
< 0.4), we applied generalized
linear regression analyses weighted for the correlation be-
tween the instruments, as previously described.
26
This rel-
atively lenient LD correlation threshold allows for an
increase in proportion of variance explained and thus in
statistical power.
26,27
In sensitivity analyses, we restricted
our instrument selection to a lower LD correlation thresh-
old (r
2
< 0.1) and applied xed-eects IVW. All Mendelian
randomization associations between antihypertensive drug
classes and stroke were scaled to 10 mm Hg decrease
in SBP.
Mendelian randomization analyses might be biased due to
pleiotropic instruments. As measures of pleiotropy, we
Table 1 Descriptive characteristics of the genome-wide association study (GWAS) meta-analyses that were included in
this Mendelian randomization study
Study stage GWAS Phenotype Sample size Ancestry Adjustments
a
Instrument selection ICBP and UK Biobank
19
SBP, DBP 757,601 individuals European Age, sex, BMI
Use of instruments for
sensitivity analysis
UK Biobank (Neale
laboratory analysis)
39
SBP, DBP 317,756 individuals European None
Primary outcome MEGASTROKE
20
Any stroke, IS, and subtypes
(LAS, CES, SVS)
67,162 cases/
454,450 controls
Multiancestry/
European
Age, sex
Primary outcome ISGC ICH GWAS
30
ICH and subtypes (lobar,
deep ICH)
1,545 cases/1,481
controls
European Age, sex
Etiologically related
outcome
UK Biobank WMH volume 10,597 individuals European Age, sex
Abbreviations: BMI = body mass index; CES = cardioembolic stroke; DBP = diastolic blood pressure; ICBP = International Consortium for Blood Pressure;ICH=
intracerebral hemorrhage; IS = ischemic stroke; ISGC = International Stroke Genetics Consortium; LAS = large artery stroke; SBP = systol ic blood pressure; SVS
= small vessel stroke; WMH = white matter hyperintensities.
a
All GWAS studies have further adjusted for principal components.
Figure 1 Selection strategy for genetic variants used as
proxies for antihypertensive drug classes
Steps for genetic instrument selection and the respective criteria and
resources. ACC = American College of Cardiology; AHA = American Heart
Association; CES = cardioembolic stroke; ESC = European Society of Cardi-
ology; ESH = European Society of Hypertension; GWAS = genome-wide as-
sociation studies; ICBP = International Consortium for Blood Pressure; ICH =
intracerebral hemorrhage; LAS = large artery stroke; MR = Mendelain ran-
domization; SBP = systolic blood pressure; SVS = small vessel stroke; UKB =
UK Biobank; WMH = white matter hyperintensity.
Neurology.org/N Neurology | Volume 95, Number 4 | July 28, 2020 3
assessed heterogeneity across Mendelian randomization
estimates with I
2
and the Cochran Q test (I
2
> 50% and p<
0.05 were considered statistically signicant)
34
and the in-
tercept obtained from Mendelian randomizationEgger re-
gression (p< 0.05 considered statistically signicant).
35
We
further used alternative methods (weightedmedian esti-
mator,
36
Mendelian randomizationEgger,
35
weighted
modal estimator
37
) with relaxing assumptions regarding
pleiotropic variants. The weighted median estimator
requires that at least half of the information for the Men-
delian randomization analysis comes from valid instru-
ments.
36
Mendelian randomizationEgger regression
requires that the strengths of potential pleiotropic instru-
ments are independent of their direct associations with the
outcome.
35
The weighted modal estimator provides correct
estimates under the assumption that a plurality of genetic
variants are valid instruments.
37
We further tested for the
presence of pleiotropic outlier variants using the Mendelian
randomization pleiotropy residual sum and outlier (MR-
PRESSO) test
38
and in sensitivity IVW Mendelian ran-
domization analyses excluded these variants.
The genetic association estimates used in the analyses for
BP were corrected for antihypertensive medication use and
were adjusted for body mass index,
19
thus introducing po-
tential bias due to medication noncompliance or collider
eects, respectively. Thus we performed sensitivity analyses
using unadjusted estimates for BP from a UKB GWAS
(317,756 individuals).
39
To minimize ancestral mismatch
with the European population used in the BP GWAS, in
sensitivity analyses we further restricted our Mendelian
randomization analyses for stroke to the MEGASTROKE
European subset.
Statistical signicance for all analyses was set at a 2-sided p
value <0.05. To examine whether BP dierentially associated
with stroke subtypes or whether there were dierential eects
of antihypertensive drugs on stroke risk, we compared the
derived odds ratios (ORs) by computing zscore for the dif-
ferences of their natural logarithms. All statistical analyses
were undertaken in R (v3.5.0; The R Foundation for Statis-
tical Computing) using the MendelianRandomization, Two-
SampleMendelian randomization, and MR-PRESSO
packages.
Data availability
This study was based on summary statistics. The GWAS data
from the ICBP and UKB meta-analysis are publicly available
through the GRASP repository of the National Heart, Lung,
and Blood Institute (grasp.nhlbi.nih.gov/FullResults.aspx).
The data from the GWAS studies for stroke and ICH are
publicly available and may be accessed through the MEGA-
STROKE (megastroke.org/download.html) and the ISGC
(cerebrovascularportal.org/informational/downloads) web-
sites, respectively. Data from the UKB GWAS for WMH
volume may be accessed through an application to UKB. The
summary data for the genetic instruments used for the
purposes of the current study are available in tables e-1 to e-3
(doi.org/10.5061/dryad.dfn2z34wj).
Results
Genetically determined BP and risk of
stroke subtypes
We rst examined the relationship between genetically de-
termined BP and the risk of stroke and stroke subtypes. We
identied 462 genetic variants associated with SBP and 460
variants associated with DBP. F statistic was >10 for all
variants, indicating low risk of weak instrument bias (tables
e-1 and e-2, doi.org/10.5061/dryad.dfn2z34wj). Mendelian
randomization analyses showed statistically signicant
associations of both SBP and DBP with risk of any stroke,
ischemic stroke, and all of its major subtypes (LAS, CES,
SVS), ICH, and deep ICH, but not lobar ICH (gure 2). The
eects of genetically determined BP were larger for LAS and
SVScomparedtoCES(pfor LAS-CES comparisons of ORs
=2×10
8
for SBP and 0.004 for DBP; pfor SVS-CES
comparisons of ORs = 0.001 for SBP and 9 × 10
4
for DBP),
and for deep compared to lobar ICH (pfor comparisons of
ORs = 0.016 for SBP and 0.009 for DBP), as depicted in
gure 2.
The eect estimates remained stable in the weighted median,
MR-Egger, and weighted-modal analyses, analyses excluding
outliers detected with MR-PRESSO, European-restricted
analyses, and analyses based on unadjusted BP estimates
(table e-5, doi.org/10.5061/dryad.dfn2z34wj). Tests for
heterogeneity and the MR-Egger intercepts were not signi-
cant in any of the analyses (I
2
< 50% and p> 0.05, re-
spectively), providing no evidence for pleiotropy.
Genetic proxies for antihypertensive drugs and
risk of stroke subtypes
Next, we selected BP-lowering variants in genes encoding
drug targets as proxies for the eects of antihypertensive drug
classes, as detailed in gure 1 and as has been previously
described,
18
and examined their eects on stroke in Mende-
lian randomization analyses. We identied 8 proxies (var-
iants) for BBs and 60 proxies for CCBs (table e-3, doi.org/10.
5061/dryad.dfn2z34wj). We further identied a single proxy
for angiotensin-converting enzyme (ACE) inhibitors, which
we did not consider in the following analyses given the lack of
power. A 10-mm Hg reduction in SBP through variants in
genes encoding targets of CCBs, but not BBs, was associated
with a signicantly lower risk of any stroke and ischemic
stroke (gure 3). In analyses for ischemic stroke subtypes, we
found a 10-mm Hg reduction in SBP through CCB variants to
be associated with signicantly lower risks of LAS, CES, and
SVS. The eect for SVS was stronger than that for both LAS
(pfor comparison of ORs = 0.002) and CES (pfor com-
parison of ORs = 6 × 10
4
)(gure 3). BB variants were not
associated with any of the ischemic stroke subtypes. We found
no signicant associations for any of the drug classes for ICH
4Neurology | Volume 95, Number 4 | July 28, 2020 Neurology.org/N
and its subtypes, which is probably related to limited power
(table e-6, doi.org/10.5061/dryad.dfn2z34wj).
Sensitivity analyses for BBs and CCBs restricted to the set of
variants with a more stringent LD threshold (r
2
< 0.1) showed
consistent association estimates with the primary analyses for
all of the examined phenotypes (table e-6, doi.org/10.5061/
dryad.dfn2z34wj). For CCBs, we found no evidence for
pleiotropy (heterogeneity: I
2
< 50%; pof MR-Egger inter-
cepts > 0.05). There was heterogeneity in the associations of
BBs with any stroke (I
2
= 59%), ischemic stroke (I
2
= 67%),
and SVS (I
2
= 66%), which was however attenuated following
exclusion of 2 outlier SNPs in MR-PRESSO (I
2
= 0%, fol-
lowing exclusion of outlier SNPs), while the association
estimates remained stable (table e-6, doi.org/10.5061/dryad.
dfn2z34wj). The results remained consistent across the al-
ternative Mendelian randomization methods (table e-6, doi.
org/10.5061/dryad.dfn2z34wj).
Genetically determined BP and WMH volume
To gain additional insight into the relationship between
genetically determined BP and cerebral SVD, we next cal-
culated Mendelian randomization estimates for the associ-
ations of BP with WMH volume. We found genetically
elevated SBP and DBP to be signicantly associated with
higher WMH volume (gure 4A). Examining the eects of
genetic proxies for antihypertensive drug classes (gure 4B),
we found signicant associations of CCBs with lower WMH
volume (β=0.491, 95% condence interval 0.591 to
0.391, p= 3.5 × 10
7
), whereas proxies for BBs were not
associated with WMH volume. The results were consistent
across sensitivity analyses (table e-5, doi.org/10.5061/
dryad.dfn2z34wj).
Discussion
We investigated the relationship between the leading modi-
able risk factor for stroke and etiologically dened stroke
subtypes by leveraging large-scale genetic data. We found
Figure 2 Mendelian randomization associations between genetically determined blood pressure and risk of stroke and
stroke subtypes
Results from the fixed-effects inverse variance weighted analysis. CI = confidence interval; DBP = diastolic blood pressure; OR = odds ratio; SBP = systolic blood
pressure.
Figure 3 Mendelian randomization associations between
genetic proxies for antihypertensive drug classes
and risk of stroke and stroke subtypes
Results from the Mendelian randomization analysis adjusting for correla-
tion between variants. BB = β-blockers; CCB = calcium channel blocker; CI =
confidence interval; OR = odds ratio; SBP = systolic blood pressure.
Neurology.org/N Neurology | Volume 95, Number 4 | July 28, 2020 5
genetic predisposition to higher BP to be associated with
greater risk of any stroke, ischemic stroke, each of its main
subtypes, and deep but not lobar ICH. Risk was higher for
LAS and SVS compared to CES. Using genetic proxies for
dierent antihypertensive drug classes, we found BP-lowering
through CCBs, but not BBs, to be associated with lower risk of
stroke and ischemic stroke. CCB variants were associated with
a lower risk of all major ischemic stroke subtypes, showing
particularly strong eects on SVS and the related phenotype
of WMH.
Our study provides evidence for a causal eect of higher BP on
LAS, CES, and SVS, thus demonstrating a broad involvement
of BP in the pathogenesis of ischemic stroke. Of note, however,
we found the eects on stroke risk to vary depending on stroke
mechanisms. Specically, risk was more pronounced for LAS
and SVS than for CES and was restricted to deep ICH. Unlike
deep ICH, lobar ICH is often related to cerebral amyloid
angiopathy and the absence of an association signal between BP
and lobar ICH is consistent with observational data.
40,41
As
demonstrated by our drug target analyses, the eects of specic
antihypertensive drug classes also diered according to stroke
subtype. Collectively, these data emphasize the need to con-
sider stroke etiologies when studying the eects of BP on stroke
risk in observational and interventional studies.
Among the major ndings is a benet of BP lowering through
genetic proxies for CCBs over BBs for SVS and the related
phenotype of WMH. In contrast, we found no disparity in
eects between genetic proxies for CCBs and BBs for LAS and
CES. This suggests that CCBs may be particularly eective in
preventing manifestations of cerebral SVD. The mechanisms
underlying this observation are unknown but may include
direct eects of CCBs on cerebral microvessels or systemic
eects, for instance, from the established inuence of CCBs
on BP variability.
9,10,42
Patients with cerebral SVD mark a population at increased
risk for stroke, dementia, and death.
43
SVD manifestations are
highly prevalent in the aging population, with gures reaching
up to 90% in patients aged 65 years and above.
44
Yet there
have been no informative trials on specic antihypertensive
agents for the prevention of SVS, WMH, or other manifes-
tations of SVD.
4547
Our Mendelian randomization results
suggest that BP lowering with CCBs should be tested in
clinical trials for prevention of SVS and other outcomes re-
lated to SVD.
The consistency of our results for stroke obtained from ge-
netic proxies for dierent drug classes with those from pre-
vious RCTs
7,9,10
is worth noting and lends condence to our
ndings on etiologic stroke subtypes for which no data from
RCTs exist. The disparity in treatment eects between CCBs
and BBs on stroke risk has been related to the opposite actions
of these drugs on BP variability; CCBs decrease whereas BBs
increase BP variability.
9,10
However, whether the eects of BP
variability on stroke risk vary by stroke etiology is unresolved
and deserves further investigation.
Our study has several methodologic strengths. We used large
datasets oering sucient statistical power for most analyses
and applied multiple methods to exclude pleiotropic eects
and other biases. We also examined phenotypes etiologically
related to stroke subtypes and performed mediation analyses
Figure 4 Mendelian randomization associations of (A) genetically determined blood pressure and (B) genetic proxies for
antihypertensive drug classes with WMH volume
Results from (A) the fixed effects inverse variance weighted
analysis and (B) Mendelian randomization analysis adjust-
ing for correlation between variants. BB = beta blockers;
CCB = calcium channel blockers; CI = confidence interval;
DBP = diastolic blood pressure; SBP = systolic blood
pressure.
6Neurology | Volume 95, Number 4 | July 28, 2020 Neurology.org/N
that allowed inferences on mechanistic aspects regarding the
association of BP with stroke. Finally, we used genetic proxies
for antihypertensive drug classes that have been validated
previously and have shown comparable eects to those de-
rived from RCTs.
18
Our study also has limitations. First, Mendelian randomization
examines the lifetime eects of genetically determined BP,
which might dier from the eect of a clinical intervention for
BP lowering. Second, based on our selection criteria, we
identied only a single genetic proxy for ACE inhibitors that
did not oer sucient statistical power to perform meaningful
analyses. Future studies encompassing larger GWAS datasets
for BP might identify such variantsand might thus oer deeper
insights into dierential eects between dierent classes of BP-
lowering agents including ACE inhibitors, angiotensin-receptor
blockers, and thiazide diuretics on stroke and stroke subtypes.
Third, by design, we could not examine nonlinear associations
between BP and stroke risk.
48
However, current evidence
suggests that the association of midlife SBP and DBP with
stroke seems to follow a linear pattern.
49
Fourth, our results
apply stroke incidence and not stroke recurrence. While we
found high BP to not be associated with risk of lobar ICH,
hypertension has been shown in observational studies to in-
crease the risk for both deep and lobar ICH recurrence,
50
which
could not be examined in the context of the current study. Fifth,
the small sample size for the ICH GWAS did not oer sucient
power to examine the eects of antihypertensive drug classes
on any, lobar, and deep ICH. Sixth, our GWAS data for BP
were restricted to individuals of European ancestry, which
could limit generalizability of our ndings to this population.
This might specically apply for ICH
30
given the evidence from
observational studies for dierential associations of BP with
lobar ICH depending on ethnicity.
51
Furthermore, there is
evidence for dierential responses to antihypertensive drug
classes by ethnicity, which could not be examined in the current
study.
52
The availability of large-scale GWAS data from more
diverse populations with higher representation of non-
European ethnicities will enable future Mendelian randomiza-
tion studies to explore potential ethnic disparities in more
detail. Finally, it was not possible to disentangle the eects of
dihydropyridine and nondihydropyridine CCBs with Mende-
lian randomization, because the dierences in the subunits of
the voltage-gated calcium channels that are the targets of these
drug subclasses in the vessels and the heart, respectively, are
encoded by the same genes but are the result of alternative
splicing.
53
We provide evidence for a causal association of higher BP
with risk of any stroke and all stroke subtypes except lobar
ICH, with a higher risk of large artery stroke and SVS
compared to cardioembolic stroke. Our ndings support
CCBs, but not BBs, to lower ischemic stroke risk. Genetic
proxies for the eects of CCBs showed particularly strong
associations with SVS and WMH, highlighting calcium
channel blockade as a promising strategy for the prevention
of cerebral SVD.
Acknowledgment
This research has been conducted using the UK Biobank
resource (UK Biobank application 2532). The authors thank
the contributions by the MEGASTROKE Consortium, Woo
et al. for the ICH GWAS meta-analysis, the ICBP
Consortium, the CHARGE Consortium, the AFGen Con-
sortium, and the Neale laboratory for performing GWAS
analyses in the UK Biobank data. MEGASTROKE has
received funding from the sources, detailed at megastroke.
org/acknowledgments.html. All MEGASTROKE authors and
their aliations are available at megastroke.org/authors.html.
Study funding
M. Georgakis is funded by scholarships from the German
Academic Exchange Service (DAAD) and Onassis Founda-
tion. D. Gill is funded by the Wellcome Trust. P. Elliott
acknowledges support from the Medical Research Council
and Public Health England (Mendelian randomization/
L01341X/1) for the C-PHE Centre for Environment and
Health. P. Elliott is supported by the UK Dementia Research
Institute, which receives its funding from UK DRI Ltd. funded
by the UK Medical Research Council, Alzheimers Society,
and Alzheimers Research UK; and the National Institute of
Health Research Imperial College Biomedical Research
Centre. P. Elliott is associate director of the Health Data
Research UK London funded by a consortium led by the UK
Medical Research Council. This project has received funding
from the European Unions Horizon 2020 research and in-
novation programme (no. 666881), SVDs@target (to M.
Dichgans), and no. 667375, CoSTREAM (to M. Dichgans);
the DFG as part of the Munich Cluster for Systems Neurology
(EXC 1010 SyNergy) and the CRC 1123 (B3) (to M.
Dichgans); the Corona Foundation (to M. Dichgans); the
Fondation Leducq (Transatlantic Network of Excellence on
the Pathogenesis of Small Vessel Disease of the Brain) (to M.
Dichgans); the e:Med program (e:AtheroSysMed) (to M.
Dichgans); and the FP7/20072103 European Union project
CVgenes@target (grant agreement number Health-F2-2013-
601456) (to M. Dichgans).
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
Publication history
Received by Neurology June 28, 2019. Accepted in nal form
January 5, 2020.
Appendix Authors
Name Location Contribution
Marios K.
Georgakis,
MD
LMU Munich,
Germany
Concept and design; data acquisition,
analysis, and interpretation; statistical
analysis; drafting of the manuscript;
critical revision of the manuscript for
intellectual content
Continued
Neurology.org/N Neurology | Volume 95, Number 4 | July 28, 2020 7
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Appendix (continued)
Name Location Contribution
Dipender
Gill, MD
Imperial
College
London, UK
Concept and design; data acquisition,
analysis, and interpretation; statistical
analysis; critical revision of the
manuscript for intellectual content
Alastair J.S.
Webb, DPhil
University of
Oxford, UK
Data acquisition, analysis, and
interpretation; critical revision of the
manuscript for intellectual content
Evangelos
Evangelou,
PhD
University of
Ioannina,
Greece
Data acquisition, analysis, and
interpretation; critical revision of the
manuscript for intellectual content
Paul Elliott,
PhD
Imperial
College
London, UK
Data acquisition, analysis, and
interpretation; critical revision of the
manuscript for intellectual content
Cathie L.M.
Sudlow,
DPhil
University of
Edinburgh, UK
Data acquisition, analysis, and
interpretation; critical revision of the
manuscript for intellectual content
Abbas
Dehghan,
MD
Imperial
College
London, UK
Data acquisition, analysis, and
interpretation; critical revision of the
manuscript for intellectual content
Rainer Malik,
PhD
LMU Munich,
Germany
Concept and design; data acquisition,
analysis, and interpretation; statistical
analysis; critical revision of the
manuscript for intellectual content
Ioanna
Tzoulaki,
PhD
Imperial
College
London, UK
Concept and design; data acquisition,
analysis, and interpretation; statistical
analysis; critical revision of the
manuscript for intellectual content
Martin
Dichgans,
MD
LMU Munich,
Germany
Concept and design; data
acquisition, analysis, and
interpretation; drafting of the
manuscript; critical revision of the
manuscript for intellectual content
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Neurology.org/N Neurology | Volume 95, Number 4 | July 28, 2020 9
... In contrast to conventional MR for an exposure, the instrument proxying drug effects in MR can be constructed based on the drug target genes, rather than genetic variants from across the genome [14]. Using genetic variants in the drug target genes as proxies [15][16][17][18], we examined the role of ACE inhibitors, BBs and CCBs in diabetes and metabolic traits in people of both European and East Asian ancestries based on the large genome-wide association studies (GWAS). ...
... Exposure For the genetic instruments in European participants, we used genetic proxies for ACE inhibitors, BBs and CCBs provided by previous studies [15][16][17][18]. Specifically, previous studies identified the genes encoding pharmacological targets for these antihypertensive drugs in DrugBank (ACE for ACE inhibitors, ADRB1 for BBs, and CACNA1D, CACNA1F, CACNA2D1, CACNA2D2, CACNA1S, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1 and CACNA1C for CCBs) [16,17]. ...
... Exposure For the genetic instruments in European participants, we used genetic proxies for ACE inhibitors, BBs and CCBs provided by previous studies [15][16][17][18]. Specifically, previous studies identified the genes encoding pharmacological targets for these antihypertensive drugs in DrugBank (ACE for ACE inhibitors, ADRB1 for BBs, and CACNA1D, CACNA1F, CACNA2D1, CACNA2D2, CACNA1S, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1 and CACNA1C for CCBs) [16,17]. Genetic variants that are present in these genes or regulatory gene regions, and also associated with systolic BP (SBP) in GWAS meta-analysis of UK Biobank and data from the International Consortium of Blood Pressure, were selected as proxies for the antihypertensive drug. ...
Article
Full-text available
Aims/hypothesis Diabetes and hyperlipidaemia are common comorbidities in people with hypertension. Despite similar protective effects on CVD, different classes of antihypertensive drugs have different effects on CVD risk factors, including diabetes, glucose metabolism and lipids. However, these pleiotropic effects have not been assessed in long-term, large randomised controlled trials, especially for East Asians. Methods We used Mendelian randomisation to obtain unconfounded associations of ACE inhibitors, β-blockers (BBs) and calcium channel blockers (CCBs). Specifically, we used genetic variants in drug target genes and related to systolic BP in Europeans and East Asians, and applied them to the largest available genome-wide association studies of diabetes (74,124 cases and 824,006 controls in Europeans, 77,418 cases and 356,122 controls in East Asians), blood glucose levels, HbA1c, and lipids (LDL-cholesterol, HDL-cholesterol and triacylglycerols) (approximately 0.5 million Europeans and 0.1 million East Asians). We used coronary artery disease (CAD) as a control outcome and used different genetic instruments and analysis methods as sensitivity analyses. Results As expected, genetically proxied ACE inhibition, BBs and CCBs were related to lower risk of CAD in both ancestries. Genetically proxied ACE inhibition was associated with a lower risk of diabetes (OR 0.85, 95% CI 0.78–0.93), and genetic proxies for BBs were associated with a higher risk of diabetes (OR 1.05, 95% CI 1.02–1.09). The estimates were similar in East Asians, and were corroborated by systematic review and meta-analyses of randomised controlled trials. In both ancestries, genetic proxies for BBs were associated with lower HDL-cholesterol and higher triacylglycerols, and genetic proxies for CCBs were associated with higher LDL-cholesterol. The estimates were robust to the use of different genetic instruments and analytical methods. Conclusions/interpretation Our findings suggest protective association of genetically proxied ACE inhibition with diabetes, while genetic proxies for BBs and CCBs possibly relate to an unfavourable metabolic profile. Developing a deeper understanding of the pathways underlying these diverse associations would be worthwhile, with implications for drug repositioning as well as optimal CVD prevention and treatment strategies in people with hypertension, diabetes and/or hyperlipidaemia. Graphical abstract
... Consistent with previous MR studies [18][19][20] , and trials 21,22 , higher systolic and diastolic BP were associated with higher risk of CVD. Multivariable MR showed that higher systolic BP was associated with higher risk of CVD overall and by subtype. ...
... However, adjusting for potential common causes, such as education, smoking and BMI, did not change the estimates. A previous MR using genetic predictors of BP without adjustment for BMI showed similar univariable MR estimates for BP on stroke 19 . Our sensitivity analysis provides similar reassurance. ...
Article
Full-text available
The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guidelines lowered the hypertension threshold to ≥ 130/80 mmHg, but the role of diastolic BP remains contested. This two-sample mendelian randomisation study used replicated genetic variants predicting systolic and diastolic BP applied to the UK Biobank and large genetic consortia, including of cardiovascular diseases and parental lifespan, to obtain total and direct effects. Systolic and diastolic BP had positive total effects on CVD (odds ratio (OR) per standard deviation 2.15, 95% confidence interval (CI) 1.95, 2.37 and OR 1.91, 95% CI 1.73, 2.11, respectively). Direct effects were similar for systolic BP (OR 1.83, 95% CI 1.48, 2.25) but completely attenuated for diastolic BP (1.18, 95% CI 0.97, 1.44), although diastolic BP was associated with coronary artery disease (OR 1.24, 95% CI 1.03, 1.50). Systolic and diastolic BP had similarly negative total (− 0.20 parental attained age z-score, 95% CI − 0.22, − 0.17 and − 0.17, 95% CI − 0.20, − 0.15, respectively) and direct negative effects on longevity. Our findings suggest systolic BP has larger direct effects than diastolic BP on CVD, but both have negative effects (total and direct) on longevity, supporting the 2017 ACC/AHA guidelines lowering both BP targets.
... Thus, the inverse association of genetically determined height with LDL cholesterol levels in both UKB and CKB could explain some of the inverse associations of height with largeartery stroke and, to a lesser extent, with small-vessel stroke, although the mechanism by which height might cause this is unclear. Genetically determined taller height was also associated with lower mean levels of blood pressure in both studies (about 1 mm Hg lower in UKB, but only 0.1 mm Hg in CKB; Table 1); based on the UKB effect, this would be expected to translate to about 3% proportional lower risk of ischemic stroke and 2% to 5% proportional lower risk of each ischemic stroke subtype [28]. By contrast with the consistency of the genetic associations, the observational associations were not as consistent between UKB and CKB, possibly reflecting differences in residual confounding in the observational analyses (e.g., by socioeconomic factors, as blood pressure and height are positively correlated with income in China [29]) or reverse causality (e.g., due to LDL-lowering medication), illustrating the advantage of MR analyses. ...
Article
Full-text available
Background Taller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke. Methods and findings Height-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations. Conclusions The findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.
... Strengths of this analysis include the use of cis-acting variants in genes encoding antihypertensive drug targets to proxy inhibition of these targets, which should minimize confounding, the employment of various sensitivity analyses to rigorously assess for violations of mendelian randomization assumptions, and the use of a summary-data mendelian randomization approach, which permitted us to leverage large-scale genetic data from several cancer GWAS consortia, enhancing statistical power and precision of causal estimates. As with prior mendelian randomization analyses of antihypertensive drug targets that used similar approaches to instrument construction to our analysis, the general concordance of estimates of the effect of these instruments on cardiometabolic endpoints with those reported in prior clinical trials for these medications supports the plausibility of these instruments [78,79]. Finally, the use of germline genetic variants as proxies for antihypertensive drug targets facilitated evaluation of the effect of the long-term inhibition of these targets, which may be more representative of the typically decades-long use of antihypertensive therapy as compared to periods of medication use typically examined in conventional observational studies and randomized trials. ...
Article
Full-text available
Background: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. Methods and findings: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. Conclusions: In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.
... Reducing abnormally high pulsatile stress in cerebral and renal small vessels may lead to an improvement in the risk of stroke. Studies on the effects of calcium channel blockers and angiotensin converting-enzyme inhibitors, which reduce arterial stiffness and hence pulsatile stress, have shown evidence of superiority to conventional diuretics and β-blockers in progression of microvascular disease (103)(104)(105). ...
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Observational studies have reported inconsistent associations between circulating lipids and breast cancer risk. Using results from >400,000 participants in two-sample Mendelian randomization, we show that genetically raised LDL-cholesterol is associated with higher risk of breast cancer (odds ratio, OR, per standard deviation, 1.09, 95% confidence interval, 1.02-1.18, P = 0.020) and estrogen receptor (ER)-positive breast cancer (OR 1.14 [1.05-1.24] P = 0.004). Genetically raised HDL-cholesterol is associated with higher risk of ER-positive breast cancer (OR 1.13 [1.01-1.26] P = 0.037). HDL-cholesterol-raising variants in the gene encoding the target of CETP inhibitors are associated with higher risk of breast cancer (OR 1.07 [1.03-1.11] P = 0.001) and ER-positive breast cancer (OR 1.08 [1.03-1.13] P = 0.001). LDL-cholesterol-lowering variants mimicking PCSK9 inhibitors are associated (P = 0.014) with lower breast cancer risk. We find no effects related to the statin and ezetimibe target genes. The possible risk-promoting effects of raised LDL-cholesterol and CETP-mediated raised HDL-cholesterol have implications for breast cancer prevention and clinical trials.
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High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10⁻³⁷), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10⁻¹²). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
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Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.
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Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study. Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data. Results: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls. Conclusions: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.
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Importance: Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated. Objective: To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. Data source: We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. Study selection: Data were taken from prospective, longitudinal cohort studies including 50 or more adults. Data extraction and synthesis: We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines. Main outcomes and measures: Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. Results: Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation. Conclusions and relevance: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI.
Article
Objective: APOE ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately white populations; we sought to evaluate whether this held true among black and Hispanic populations. Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage study is a prospective, multicenter case-control study of ICH among white, black, and Hispanic participants. Controls were recruited to match cases based on age, ethnicity/race, sex, and geographic location. APOE genotyping and ICH location was determined blinded to clinical data. Results: There were 907 cases of lobar ICH and 2,660 controls with APOE results. Both APOE ε2 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0, p = 0.01) and APOE ε4 (OR 2.0, 95% CI 1.5-2.6, p < 1 × 10-4) were associated with lobar ICH among white participants. Among black participants, neither APOE ε2 (OR 1.0, 95% CI 0.7-1.5, p = 0.97) nor APOE ε4 (OR 1.0, 95% CI 0.7-1.4, p = 0.90) were independent risk factors for lobar ICH. Similarly, among Hispanic participants, neither APOE ε2 (OR 1.0, 95% CI 0.6-1.8, p = 0.89) nor APOE ε4 (OR 1.2, 95% CI 0.8-1.7, p = 0.36) were associated with lobar ICH. Hypertension was a significant risk factor for lobar ICH in all 3 racial/ethnic groups. Conclusion: In contrast to Caucasian patients, in which amyloid risk factors predominate in lobar ICH, we found that hypertension was the predominant risk factor for lobar ICH. While APOE alleles are a risk factor for lobar ICH in white patients, they appear to have a much lower effect in lobar ICH in African American and Hispanic American populations. This suggests APOE ε2 and APOE ε4 do not affect lobar ICH risk homogeneously across ethnic populations. In addition, hypertension has a prominent role in lobar ICH risk, particularly among minorities.