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Catechol-O-Methyltransferase and Cardiovascular Disease: MESA

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Background Genetic variation in catechol‐O‐methyltransferase ( COMT ), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease ( CVD ) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD , and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima‐media thickness in MESA (Multi‐Ethnic Study of Atherosclerosis). In 65 957 person‐years of follow‐up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74–0.97 [ P =0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, −3.65; SE , 1.35 mg/ dL [ P =0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65–0.95; P =0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71–1.13; P =0.34) among more frequent users ( P interaction =0.39). Neither intima‐media thickness nor coronary artery calcium was associated with COMT . Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD .
Catechol-O-Methyltransferase and Cardiovascular Disease: MESA
Kathryn T. Hall, PhD, MPH; Elisabeth Battinelli, MD, PhD; Daniel I. Chasman, PhD; Paul M Ridker, MD, MPH; Bruce M. Psaty, MD, PhD;
Jerome I. Rotter, MD; Ted J. Kaptchuk, BA; Russell P. Tracy, PhD; Christina L. Wassel, PhD; Kenneth J. Mukamal, MD, MPH
Background-Genetic variation in catechol-O-methyltransferase (COMT), a key enzyme in estrogen and catecholamine
metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Womens Health
Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not
aspirin, suggesting a possible role of COMT in thrombosis.
Methods and Results-To evaluate potential pathways linking COMT with CVD, andCO MT effect modicationof aspirin in prevention, we
examined COMT association with CVD risk and subclinical measures,coronary artery calcium, and carotid intima-media thickness in MESA
(Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was
associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.740.97 [P=0.02]). This association remained virtually unchanged after
adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (b,3.65; SE, 1.35 mg/dL [P=0.007]).
Results were directionally similar but not signicant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95%
CI, 0.650.95; P=0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.711.13; P=0.34) among more frequent
users (P
interaction
=0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT.
Conclusions-In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD
risk and lower brinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible
role of COMT in the latter stages of CVD. (J Am Heart Assoc. 2019;8:e014986. DOI: 10.1161/JAHA.119.014986.)
Key Words: aspirin cardiovascular disease risk factors catecholamine catecholaminergic polymorphic ventricular
tachycardia catechol-O-methyltransferase
Genetic variation in catechol-O-methyltransferase
(COMT), a key enzyme in catecholamine metabolism,
has plausible physiological links to both cardiovascular
disease (CVD) and its risk factors.
1
COMT metabolizes
catechol estrogen and the catecholamines epinephrine,
norepinephrine, and dopamine by catalyzing the transfer of
a methyl group from S-adenosyl methionine onto the catechol
moieties.
2
COMT links to estrogen regulation are made more
complex by the presence of estrogen receptor response
elements in the COMT promoter region,
3
and the downreg-
ulatory effects of estradiol on COMT.
4
These estradiol effects
are thought to contribute to sexual variation in COMT effects,
with lower activity in women compared with men.
5,6
COMT is
expressed in platelets,
7
and the highest levels are expressed
in the liver and adrenal glands.
8
COMTs roles in reducing the
toxic effects of catechol estrogen exposure and cate-
cholamine ux are important in maintaining cardiovascular
and renal function. Hence, rs4818 and rs4680, genetic single
nucleotide polymorphisms (SNPs) in COMT, have been
associated with CVD,
1,9
hypertension,
1,1013
type 2 diabetes
mellitus,
14,15
and preeclampsia.
16,17
The rs4680 variant
encodes a functional G (Val) to A (Met) substitution that
results in a 3- to 4-fold reduction in COMT enzyme activity.
Both rs4680 and rs4818 disrupt stability of COMT mRNA and
have effects related to COMT mRNA secondary structure and
gene expression.
18
We previously demonstrated that both of
From the Divisions of Preventive Medicine (K.T.H., D.I.C., P.M.R.) and
Hematology (E.B.), Department of Medicine, Brigham and Womens Hospital,
and Division of General Medicine and Primary Care, Beth Israel Deaconess
Medical Center (T.J.K., K.J.M.), Harvard Medical School, Boston, MA; Cardio-
vascular Health Research Unit, Department of Medicine, University of
Washington, Seattle, WA (B.M.P.); Kaiser Permanente Washington Health
Research Institute, Seattle, WA (B.M.P.); Departments of Pediatrics and
Medicine, The Institute for Translational Genomics and Population Sciences,
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,
Torrance, CA (J.I.R.); Laboratory for Clinical Biochemistry Research, University
of Vermont, College of Medicine, Colchester, VT (R.P.T.); Applied Sciences,
Premier, Inc, Charlotte, NC (C.L.W.).
Accompanying Tables S1 through S8 are available at https://www.ahajourna
ls.org/doi/suppl/10.1161/JAHA.119.014986
Correspondence to: Kathryn T. Hall, PhD, MPH, Division of Preventive
Medicine, Brigham and Womens Hospital and Harvard Medical School, 900
Commonwealth Avenue, Boston, MA 021115. E-mail: khall0@bwh.harvard.edu
Received October 17, 2019; accepted November 4, 2019.
ª2019 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modications or adaptations are made.
DOI: 10.1161/JAHA.119.014986 Journal of the American Heart Association 1
ORIGINAL RESEARCH
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these COMT variants were associated with rates of CVD in
women of European ancestry
1
in the genetics cohort of the
WHS (Womens Health Study),
19
the WGHS (Womens
Genome Health Study),
20
and men and women in CARDIo-
GRAM (Coronary Artery Disease Genome-Wide Replication
and Meta-Analysis).
21
In the WGHS and large international
consortia, COMT was also associated with several CVD risk
factors including systolic blood pressure (BP),
1
triglycerides,
and glycated hemoglobin (HbA
1c
) levels.
14,15
We also
observed a signicant COMT-aspirin interaction, such that
the statistically signicant 33% CVD protection associated
with the G alleles of rs4818 and rs4680 was attenuated with
randomized assignment to aspirin (P
interaction
<0.001), sug-
gesting that benet may result from antiplatelet activity that
is superseded by aspirin. However, the WGHS comprised a
white population of women aged 45 years or older, limiting
the generalizability of the WGHS ndings. Further, the WGHS
included few physiological measures with which to evaluate
potential pathophysiologic pathways of CVD. To address more
fully the cardiovascular effects of the COMT locus on rates of
clinical and subclinical CVD and the potential interaction with
aspirin, we studied these factors in MESA (Multi-Ethnic Study
of Atherosclerosis), an observational study of individuals of
European, African, Asian, and Hispanic ancestry free of CVD
at baseline.
Materials and Methods
Data for the National Heart, Lung, and Blood Institutes SHARe
(SNP Health Association Resource), a substudy of the MESA
cohort used in this analysis, is publically available through
dbGaP (Study Accession: phs000420.v6.p3). The methods
and materials used in this analysis are available to any
researcher for purposes of reproducing the results or
replicating the procedures.
The MESA Cohort
The MESA cohort includes 6814 participants from 6 eld
centers in the United States: Baltimore, Maryland; Chicago,
Illinois; New York, New York; Forsyth County, North Carolina;
Los Angeles, California; and St. Paul, Minnesota. Participants
self-identied as white (38%), black (28%), Asian (12%), or
Hispanic (22%). Specics of the MESA design have been
previously reported.
22
At baseline, participants were free from
CVD (as dened by physician-diagnosed angina, stroke,
myocardial infarction, transient ischemic attack, heart failure,
or resuscitated cardiac arrest). Since the initiation of the
study in 2000, participants have undergone 5 in-person
examinations: baseline (July 17, 2000 to August 29, 2002)
and 4 follow-up examinations, examination 2 (September 9,
2002, to February 7, 2004), examination 3 (March 10, 2004,
to September 16, 2005), examination 4 (September 23, 2005,
to May 30, 2007), and examination 5 (April 19, 2010, to
February 4, 2012). MESA was conducted under institutional
review board approval and oversight and with informed
consent of participants. The study was performed in accord
with the principles of the Declaration of Helsinki. This study
was conducted under institutional review board approval and
oversight from Partners HealthCare.
Outcome Measures
Our primary cardiovascular outcome was dened as myocar-
dial infarction, stroke, resuscitated cardiac arrest, and death
from stroke or coronary heart disease. We prespecied this
outcome to be similar to the composite primary CVD outcome
in the WGHS, which encompassed myocardial infarction,
stroke, or death from CVD. CVD events in MESA were
assessed at intervals of 9 to 12 months, between 2000 and
2013, by contacting participants or family members about
CVD outpatient diagnoses and procedures, hospitalizations,
and deaths. Self-reports were veried by review of death
certicates and medical records for all hospitalizations and
selected outpatient cardiovascular diagnoses and procedures.
Two MESA physicians independently reviewed and classied
events; disagreements were adjudicated by the MESA mor-
tality and morbidity review committee.
Data on CVD risk factors including smoking status, medical
history of diabetes mellitus, and hypertension were collected
using questionnaires and laboratory evaluation at each
examination. Body mass index was calculated as weight/
height (kg/m
2
). BP was determined as the average of the
Clinical Perspective
What Is New?
A common coding variant in the catechol-O-methyltransfer-
ase locus (rs4818) was associated with lower rates of
incident cardiovascular disease in MESA (Multi-Ethnic Study
of Atherosclerosis) cohort.
Two variants (rs4818 and rs4680) linked closely in white
populations exhibited much less linkage in other popula-
tions, enabling separate analyses that were generally
stronger for the former variant.
What Are the Clinical Implications?
The catechol-O-methyltransferase variant was also associ-
ated with lower levels of brinogen, but not with radio-
graphic measures of subclinical atherosclerosis, suggesting
that the underlying mechanism of action likely impacts the
latter stages of cardiovascular disease.
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COMT and Cardiovascular Disease in MESA Hall et al
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second and third measurements taken after 5 minutes of
seated rest. Laboratory measures including HbA
1c
, fasting
glucose, cholesterol, lipoprotein, and triglyceride levels were
performed on blood samples following a 12-hour fast.
Carotid intima-media thickness (IMT) was assessed at
examination 1 by B-mode ultrasonography of the right and left
near and far walls of the internal and common carotid arteries
as previously described.
23,24
Maximum IMT from examination
1 was computed as previously described by creating a
composite Zscore based on the standardized 2 carotid IMT
site measurements from the common and internal carotid
artery.
24
When only one of the measures was available, that
one was used. Coronary artery calcium (CAC) was assessed
by chest computed tomography.
24
Agatston scores of CAC
were computed from phantom-adjusted coronary artery
plaque density and area from replicate scans taken at the 5
examinations. CAC was stratied according to absolute cut
points of Agatston scores <1, 1 to 100, 101 to 400, and
>400,
25
and COMT association with these categories over the
5 MESA examinations was assessed using a repeated
measures analysis.
The medication inventory method was used to assess
aspirin use at each examination. Self-reported frequency of
aspirin use at least 3 days per week was recorded at
examinations 1 through 5.
COMT SNPs rs4818 and rs4680 were genotyped using the
Illumina CARe iSelect (IBC) chip. Of the 6814 participants in
MESA, 6316 had genotyping data available for COMT rs4818.
Statistical Analysis
Cox proportional hazard models were used to assess genetic
associations with incident CVD, stroke, and myocardial
infarction assuming a standard additive genetic model.
Models were either adjusted for age, sex, and site or fully
adjusted for the latter plus cardiovascular risk factors, which
included medical history of hypertension and diabetes
mellitus, smoking status, systolic and diastolic BP, choles-
terol, triglycerides, high-density lipoprotein levels, and brino-
gen. In all cases, we performed race/ethnicity-stratied
analyses adjusting for population substructure with 5 race-
specic principal components. COMT association with CVD
has not been studied in black and Hispanic populations.
Based on the WGHS, we estimated that we would be
adequately powered to observe a difference by COMT
genotype if the frequency of the rs4680G allele was >0.30
(Table S1). COMT expression is regulated by estrogen and
COMT is also a key enzyme in estrogen metabolism. In the
WGHS, our initial observation of COMT effects on CVD were
among white women, 44% of whom took exogenous estrogen
hormone replacement therapy (HRT). In MESA, 68% of white
women reported HRT use in examination 1. Hence, in addition
to secondary analyses stratied by sex, we conducted
sensitivity analyses in white women stratied by ever/never
use of HRT and examined potential COMT effect modication
of HRT ever/never use. For each model, the proportionality
assumption was veried. Analyses were performed in SAS 9.4
(SAS Institute).
Linear regression was used to evaluate COMT cross-
sectional associations with the IMT composite Zscore and
baseline risk factors: systolic BP, diastolic BP, low-density
lipoprotein cholesterol, high-density lipoprotein cholesterol,
fasting glucose, HbA
1c
,brinogen, and triglycerides for each
race/ethnicity subgroup and then meta-analyzed for the
overall associations. For right-skewed data (triglycerides), we
determined SE estimates using robust SEs. Models for BP and
lipids were adjusted for hypertensive and lipid-lowering
medication use, respectively. For CAC, Agatston scores were
categorized as previously described
26
and updated for each
examination. Multinomial logistic regression was used to
examine COMT cross-sectional association with CAC in
models adjusted for age, sex, site, and the rst 5 principal
components for race/ethnicity.
Modication of the COMT association with incidence of
CVD by aspirin use was tested on the Cox model coefcients
with a term corresponding to the cross-product of allele
number and aspirin use categorized as 0 (not currently used
or used <3 times per week) or 1 (used currently at least 3
times per week). Because aspirin use changed over time, and
because the proposed mechanism of action for aspirin
involves irreversible platelet inhibition, we used a simple
time-varying covariate for aspirin use that was updated at
each examination. We also conducted sensitivity analyses
stratied by HRT ever/never use specically among white
women to approximate most closely the WGHS population
previously analyzed. Individual race/ethnicity COMT and
COMT by aspirin use interaction estimates were meta-
analyzed across races using inverse variance xed effects
models in Comprehensive Meta-Analysis, version 3.3.070
(Biostat, New Jersey).
Results
Participant Characteristics
Characteristics of the study sample at baseline stratied by
race are reported in Table 1 and those stratied by rs4818
are reported in Table S2. Age and sex distributions did not
differ by race. The allele frequencies of rs4818 and rs4680
(Table S3) varied by race/ethnicity. Both SNPs were in Hardy-
Weinberg equilibrium within each race/ethnicity subgroup
(P>0.05). In the overall population, the minor allele frequen-
cies for rs4818 (G allele) and rs4680 (A(Met) allele), were 32%
and 40%, respectively. Linkage disequilibrium and correlation
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COMT and Cardiovascular Disease in MESA Hall et al
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between the COMT SNPs was strongest for whites (0.72) and
lower among others (0.120.24).
COMT Association With CVD Risk Factors and
Subclinical Disease
In meta-analyses of CVD risk factors across races/ethnicities,
only brinogen was signicantly associated with COMT
rs4818 (Table 2 and Table S4). In gene-dosage models of
brinogen, the direction of the rs4818 association was
consistent across the races/ethnicities (b,3.65 mg/dL;
SE, 1.35 [P=0.007]) and was strongest and statistically
signicant among Asians. In secondary analyses using sex-
stratied models, the rs4818 association was negative for
both women (b,5.29 mg/dL; SE, 1.93 [P=0.006]) and men
(b,2.28 mg/dL; SE, 2.98 [P=0.44]). In contrast, the overall
association of rs4680 with brinogen was null, with signicant
differences in direction between women (b,2.98 mg/dL;
SE, 1.83 [P=0.10]) and men (b, 4.19 mg/dL; SE, 1.75
[P=0.02]) (P
interaction
=0.005) (Table S4).
COMT associations with other CVD risk factors HbA
1c
,
fasting glucose, high-density lipoprotein cholesterol, and
intercellular adhesion molecule were directionally consistent
for rs4818 and rs4680 and within 2 SDs of previously
reported statistically signicant associations (Table S4).
1,14
Adjustment for BP medication or lipid medication use in lipid
and systolic and diastolic BP models were similarly null.
No statistically signicant associations with carotid artery
IMT at examination 1 were observed for COMT rs4818 (b,
0.004; SE, 0.014 [P=0.76]) and rs4680 (b,0.019; SE,
0.014 [P=0.17]) (Table 3). Further, no statistically signicant
associations were observed for COMT categories of CAC over
the 5 examinations for rs4818 (odds ratio, 1.00; 95% CI,
0.931.08 [P=0.93]) or rs4680 (odds ratio, 1.00; 95% CI,
0.931.08 [P=0.96]). These results did not differ substantively
with stratication by sex.
COMT Association With Incident CVD
MESA documented 524 primary incident CVD events during
65 957 person-years of follow-up. Consistent with our nd-
ings in the WGHS and CARDIoGRAM, the rs4818G allele was
associated with a 15% lower rate of CVD (hazard ratio [HR],
0.85; 95% CI, 0.740.97 [P=0.02]) across the 4 racial/ethnic
groups (Table 4 and FigurePanel A). The association was
directionally consistent in each of the race/ethnicity popula-
tions and signicant among Hispanics. This inverse associa-
tion with CVD risk was not attenuated by adjustment for CVD
risk factors: body mass index, triglycerides, high-density
lipoprotein, cholesterol, systolic BP, history of smoking,
diabetes mellitus, hypertension, or brinogen. The overall
direction of the rs4680 Val allele association with CVD was
consistent with rs4818 but was statistically nonsignicant
(Table 4 and FigurePanel B). No substantive changes were
observed in models adjusted for risk factors (including
brinogen) or stratied by sex (Table S5).
In the WGHS, our initial observation of COMT effects on
CVD were among white women, 43% of whom took exogenous
Table 1. Baseline Characteristics of MESA Participants Genotyped for rs4818 by Race
Race
White Black Hispanic Asian
Participants, No. (%) 2481 1639 1428 768
Age, y 62.7 (10.3) 62.2 (10.1) 61.4 (10.3) 62.3 (10.4)
Women, % 1304 (52.5) 903 (54.0) 740 (51.7) 389 (50.7)
History of diabetes mellitus, % 150 (6.8) 285 (20.2) 255 (21.2) 101 (16.0)
History of hypertension, % 967 (38.9) 989 (59.2) 603 (42.1) 288 (37.5)
Current smoker, % 286 (11.5) 306 (18.3) 192 (13.4) 44 (5.7)
Body mass index, kg/m
2
27.7 (5.1) 30.2 (5.9) 29.5 (5.2) 24.0 (3.3)
Systolic BP, mm Hg 123.6 (20.5) 131.8 (21.8) 126.9 (22.1) 124.4 (21.7)
Diastolic BP, mm Hg 70.2 (10.0) 74.6 (10.3) 71.6 (10.2) 71.9 (10.3)
HDL cholesterol, mg/dL 52.4 (15.8) 52.3 (15.2) 47.5 (13.0) 49.3 (12.4)
Triglycerides, mg/dL 133.1 (90.5) 104.9 (69.9) 158.3 (102.2) 143.2 (85.9)
Total cholesterol, mg/dL 195.8 (35.4) 189.5 (36.4) 198.3 (37.7) 192.5 (31.5)
COMT
rs4818 MAF (G) 0.41 0.21 0.27 0.33
COMT
rs4680 MAF (A) 0.51 0.31 0.39 0.28
Numbers in parentheses are expressed as SD unless otherwise indicated. BP indicates blood pressure; COMT, catechol-O-methyltransferase; HDL, high-density lipoprotein; MAF, min or
allele frequency; MESA, Multi-Ethnic Study of Atherosclerosis.
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estrogen through HRT. In MESA, use of HRT varied by race,
with white women using the most64.1% used HRT at
examination 1 (Table S6). In subset analyses among white
women in MESA stratied by HRT use, both COMT rs4680 and
rs4818G alleles were associated with higher rates of CVD
among women who had never taken HRT. Among white
women who had taken HRT, the COMT association was
protective for rs4818 and rs4680, but only statistically
signicant for rs4818 (Table S6). A test for a COMT-HRT
interaction was signicant for both SNPs (P
interaction
<0.05).
The COMT-HRT interaction was not observed among women
in the other race/ethnic subpopulations.
COMT and Aspirin
Aspirin use >3 days per week appeared to increase across
the 5 examinations, but did not vary by COMT rs4818
genotype (Table S7). When stratied by time-varying aspirin
use over the 5 examinations, the COMT rs4818G allele was
statistically signicantly associated with lower rates of CVD
among individuals who used aspirin <3 days per week (HR,
0.79; 95% CI, 0.650.95 [P=0.02]); the corresponding HR
among those who used aspirin 3 days per week was 0.89
(95% CI, 0.711.13; P=0.34 [P
interaction
=0.39]) (Table 5). There
was no difference in rates of CVD associated with COMT
rs4680 by aspirin use.
In subset analyses of white women stratied by HRT use at
examination 1 and aspirin <3 days per week, COMT rs4818
(HR, 0.34; 95% CI, 0.160.69 [P=0.004]) and rs4680 (HR,
0.46; 95% CI, 0.250.85 [P=0.01]) G alleles were associated
with lower rates of CVD. These associations were attenuated
among patients using HRT and aspirin 3 days per week, with
a signicant interaction for rs4680 but not rs4818 (Table S8).
Among white women who did not use HRT, rates of CVD were
higher with or without aspirin use.
Discussion
In MESA, we replicated our previous nding from the WGHS
and CARDIoGRAM,
5
that the COMT rs4818G allele is asso-
ciated with lower rates of CVD. This association was similar
across race/ethnicity groups and remained signicant after
Table 2. Effect Estimates and Standard Error of COMT rs4818 (Per G Allele) and rs4680 (Per Val Allele) Association With Baseline
Fibrinogen Levels (mg/dL) in Gene-Dosage Models
SNP Sex
All White Black Hispanic Asian
bSE PValue bSE PValue bSE PValue bSE PValue bSE PValue
rs4818 All 3.65 1.35 0.007 0.81 2.11 0.70 2.29 3.03 0.45 4.94 3.02 0.10 9.70 3.06 0.002
Women 5.29 1.93 0.01 4.70 4.69 0.32 2.92 4.40 0.51 3.78 2.89 0.19 11.76 4.42 0.01
Men 2.28 2.98 0.44 0.42 4.35 0.92 8.00 4.46 0.07 3.53 2.80 0.21 6.90 4.53 0.13
rs4680 All 0.53 1.29 0.68 0.84 1.96 0.67 1.70 2.78 0.54 1.43 2.89 0.62 0.54 3.31 0.87
Women 2.98 1.83 0.10 3.05 2.81 0.28 0.44 4.09 0.92 7.68 4.00 0.06 0.02 4.45 0.99
Men 4.19 1.75 0.02 5.05 2.69 0.06 4.01 3.71 0.28 5.09 4.08 0.21 1.37 4.20 0.74
COMT indicates catechol-O-methyltransferase; SNP, single nucleotide polymorphism.
Table 3. COMT rs4818 and rs4680 Gene-Dosage (Per Allele) Association With Carotid IMT Composite ZScore* and CAC Overall
and by Race
Race/Ethnicity
IMT CAC
rs4818 rs4680 rs4818 rs4680
b(SE), PValue b(SE), PValue b(SE), PValue b(SE), PValue
All 0.004 (0.014), 0.76 0.019 (0.014), 0.17 1.00 (0.931.08), 0.93 1.00 (0.931.08), 0.96
White 0.014 (0.022), 0.52 0.003 (0.021), 0.16 0.94 (0.851.05), 0.28 0.95 (0.861.06), 0.34
Black 0.006 (0.031), 0.85 0.007 (0.029), 0.81 1.06 (0.901.25), 0.46 1.05 (0.911.21), 0.54
Hispanic 0.011 (0.031), 0.73 0.006 (0.027), 0.82 1.05 (0.901.24), 0.52 1.10 (0.951.28), 0.20
Asian 0.018 (0.037), 0.62 0.027 (0.038), 0.48 1.09 (0.891.33), 0.40 0.92 (0.751.14), 0.45
*Intima-media thickness (IMT) composite Zscore is based on the standardized 2 carotid IMT site measurement from the common and internal carotid artery. CAC indicates coronary artery
calcium; COMT, catechol-O-methyltransferase.
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adjusting for CVD risk factors. The overall direction of COMT
associations with CVD risk factors tended to be consistent
with previous ndings for systolic BP,
1,1013
HbA
1c
,
14
and
triglyceride levels,
1,27
but they were not statistically signi-
cant in the smaller and more diverse MESA sample. The only
risk factor signicantly associated with COMT in MESA was
brinogen. The direction of this association was consistent
with a nonsignicant effect observed in the WGHS.
1
We did
not observe effect modication of the rs4818 association with
CVD by aspirin use. With the exception of systolic BP, these
ndings were directionally similar, but statistically nonsignif-
icant for rs4680. Further, neither COMT SNP was associated
with carotid artery IMT or CAC. In contrast to the European
ancestry of the WGHS participants, the MESA population is
representative of multiple racial/ethnic groups and consists
of both men and women. Hence, our ndings of signicant
COMT rs4818 effects on CVD in MESA allow generalization to
men, blacks, and Hispanics, where the ndings were for the
most part consistent. Among Asians, who represented the
smallest subpopulation in MESA, the main associations were
nonsignicant, although the COMT association with brinogen
in this group was signicant. Whether the modest differences
across races represent the play of chance or specic
differences in linkage by race will also require dedicated
study in larger samples.
These results were not wholly consistent with our original
observations in the WGHS where the population we examined
consisted of white women, older than 45 years, of whom 43%
reported taking estrogen HRT at baseline. In MESA, a majority
of white women (64%) reported having used HRT at exami-
nation 1. Given the modulatory effects of estrogen on COMT
gene expression and COMTs role in estrogen metabolism
(converting catechol estrogens to 2- and 4-methoxyestradiol),
we conducted stratied analyses among a subset of the MESA
cohort most similar to the WGHS population. These subset
analyses suggested that the discrepancy between the WGHS
and MESA may indeed be attributed to differences in estrogen
levels related to sex and HRT use. However, neither the WGHS
or MESA were designed to look at the inuence of COMT and
HRT on the incidence of CVD. Therefore, these ndings are
hypothesis generating and warrant examination in other
cohorts. Further, in the WGHS, the associations of rs4818 and
rs4680 with CVD were similar, as the 2 are highly linked in
most white populations. However, in the racially diverse MESA
sample, where the linkage was much weaker among nonwhite
Table 4. COMT rs4818 and rs4680 Gene-Dosage (Per
Allele*) Association With Rates of CVD in MESA
SNP Race/Ethnicity Events/No. HR (95% CI), PValue
rs4818 All, model 1
498/5984 0.85 (0.740.97), 0.02
All, model 2
497/5961 0.85 (0.740.98), 0.02
White 203/2332 0.90 (0.741.09), 0.29
Black 122/1518 0.85 (0.621.16), 0.32
Hispanic 130/1375 0.71 (0.530.95), 0.02
Asian 43/759 0.90 (0.741.09), 0.29
rs4680 All, model 1
524/6157 0.95 (0.841.08), 0.46
All, model 2
495/6066 0.96 (0.851.09), 0.56
White 214/2476 1.02 (0.841.23), 0.86
Black 130/1575 0.97 (0.751.25). 0.79
Hispanic 137/1426 0.94 (0.731.19), 0.59
Asian 43/768 0.68 (0.431.07), 0.10
*Allele key: rs4818 coded allele=G, reference=C; rs4680 coded allele=Val (G),
reference=Met (A).
Model 1: meta-analysis of Cox proportional models adjusted for age, sex, race, site, and
the rst 5 principal components specic to each of the 4 race/ethnicities.
Model 2: meta-analysis of Cox proportional models adjusted for time-varying
cardiovascular disease (CVD) risk factors from examination 1 to 5: body mass index,
triglycerides, high-density lipoprotein, low-density lipoprotein, cholesterol, systolic blood
pressure and history of smoking, diabetes mellitus, and hypertension in addition to age,
sex, race, and the rst 5 principal components specic to each of the 4 race/ethnicities.
COMT indicates catechol-O-methyltransferase; HR, hazard ratio; MESA, Multi-Ethnic
Study of Atherosclerosis; SNP, single nucleotide polymorphism.
A
B
Figure. KaplanMeier curves of cardiovascular disease event-
free survival probability over the duration of MESA (Multi-Ethnic
Study of Atherosclerosis) (in years) by catechol-O-methyltransfer-
ase (COMT)(A) rs4818 and (B) rs4680 genotypes.
DOI: 10.1161/JAHA.119.014986 Journal of the American Heart Association 6
COMT and Cardiovascular Disease in MESA Hall et al
ORIGINAL RESEARCH
Downloaded from http://ahajournals.org by on December 17, 2019
participants, the CVD association with rs4680 was not
signicant, suggesting that either rs4680 is not the causal
locus or its effects on COMT activity or gene expression levels
are potentially sensitive to estrogen. Still, much ner
mapping, and likely whole genome sequencing, in similarly
diverse samples will be needed to determine whether
variation at rs4818, which appears to disrupt mRNA stabil-
ity,
18
is the causal locus for the CVD effects observed here.
IMT and CAC have both been shown to be associated with
incident CVD in MESA and elsewhere.
28
Our ndings that
COMT was not clearly associated with either subclinical
measure suggests that this locus is likely to inuence risk of
CVD through mechanisms other than atherosclerosis. Nota-
bly, the effect estimates for intercellular adhesion molecule,
SBP, and HbA
1c
were directionally consistent with the WGHS
and the Diabetes Prevention Program,
1,14
although, in the
smaller more diverse MESA cohort, the associations were
nonsignicant. The decidedly null results for subclinical
disease, when combined with the suggestive effects for
interaction with aspirin and the observed effect on brinogen,
tend to suggest that COMT is most likely to exert its effects
on the progression of subclinical to clinical CVD rather than
on the development of subclinical disease per se.
COMT is expressed in platelets, where catecholamine ux
inuences development of thrombotic events via platelet
activation.
29
Thus, genetically derived variation in COMT
functionality could modify circulating and platelet levels of
catecholamines, in turn shifting the threshold for vascular
events. The link between COMT, platelets, and estrogen may
also contribute to its effects in cancer development.
30,31
Interestingly, the brinogen gene has a corticosteroid
response element in its regulatory region,
32
and brinogen
levels are inuenced by estrogen in women who use HRT,
33,34
pointing to a potential link between catecholamines, COMT,
and brinogen.
It is important to acknowledge that some of our results,
and especially those in smaller subgroups, had wide CIs,
reecting smaller numbers of participants and events. Results
in these smaller subgroups should be treated as hypothesis-
generating and, if possible, conrmed in other multiethnic
cohorts that may have similar information.
Conclusions
These results build upon our previous work in the WGHS in
demonstrating that common genetic variation in COMT is
associated with risk of CVD in a multiracial population of men
and women.
Sources of Funding
Hall is supported by the National Heart, Lung, and Blood
Institute (NHLBI) K01HL130625 and Harvard Catalyst |The
Harvard Clinical and Translational Science Center (National
Center for Advancing Translational Sciences, National Insti-
tutes of Health Award UL 1TR002541) and nancial contri-
butions from Harvard University and its afliated academic
healthcare centers. Kaptchuk is supported by National Center
for Complementary and Integrative Health 2K24 AT004095.
MESA and the MESA SHARe project are conducted and
supported by the NHLBI in collaboration with MESA investi-
gators. Support for MESA is provided by contracts
HHSN268201500003I, N01-HC-95159, N01-HC-95160,
N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-
95164, N01-HC-95165, N01-HC-95166, N01-HC-95167,
N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-
001079, and UL1-TR-001420 through NHLBI. The provision
of genotyping data was supported in part by the National
Center for Advancing Translational Sciences, CTSI grant
UL1TR001881, and the National Institute of Diabetes and
Digestive and Kidney Diseases Diabetes Research Center
grant DK063491 to the Southern California Diabetes
Endocrinology Research Center. Funding for SHARe
Table 5. COMT rs4818 and rs4680 Gene-Dosage (Per Allele*) Association With Rates of CVD Stratied by Aspirin Use Overall and
by Race
Race/Ethnicity
Aspirin <3 d/wk Aspirin 3 d/wk
P
interaction
HR (95% CI) PValue HR (95% CI) PValue
Overall
0.79 (0.650.95) 0.02 0.89 (0.711.13) 0.34 0.39
White 0.83 (0.611.11) 0.21 0.90 (0.661.22) 0.34 0.70
Black 0.65 (0.401.04) 0.07 1.27 (0.772.11) 0.38 0.06
Hispanic 0.70 (0.481.02) 0.06 0.65 (0.391.08) 0.10 0.81
Asian 1.09 (0.631.89) 0. 76 0.19 (0.012.40) 0.20 0.21
COMT indicates catechol-O-methyltransferase; CVD, cardiovascular disease; HR, hazard ratio.
*Allele key: rs4818 coded allele=G, reference=C.
Meta-analysis of Cox proportional models adjusted for age, sex, race, site, and the rst 5 principal components specic to each of the 4 race/ ethnicities.
DOI: 10.1161/JAHA.119.014986 Journal of the American Heart Association 7
COMT and Cardiovascular Disease in MESA Hall et al
ORIGINAL RESEARCH
Downloaded from http://ahajournals.org by on December 17, 2019
genotyping was provided by NHLBI contract N02-HL-64278.
Genotyping was performed at Affymetrix (Santa Clara, Cali-
fornia) and the Broad Institute of Harvard and MIT (Boston,
Massachusetts) using the Affymetrix Genome-Wide Human
SNP Array 6.0.
Disclosures
Psaty serves on the steering committee of the Yale University
Open Data Access Project funded by Johnson & Johnson. The
remaining authors have no disclosures to report.
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COMT and Cardiovascular Disease in MESA Hall et al
ORIGINAL RESEARCH
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SUPPLEMENTAL MATERIAL
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Table S1: Power estimates of hazard ratios for incident CVD based on rs4680 G(val) allele frequencies over range of GAF from 0.3-0.6.
GAF
HR
Power
0.30
0.70
0.98
0.75
0.91
0.80
0.74
0.40
0.70
0.99
0.75
0.95
0.80
0.80
0.50
0.70
0.99
0.75
0.96
0.80
0.83
0.60
0.70
0.99
0.75
0.96
0.80
0.82
Abbreviations: HR=Hazard Ratio; GAF= Gene allele frequency
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Table S2: Demographics, baseline characteristics and aspirin use by COMT rs4818 genotype use in MESA.
CC
GC
GG
Participants, n
2888 (47.7)
2515 (41.6)
649 (10.7)
Demographic data
Age
62.1 (10.1)
62.3 (10.4)
63.0 (10.5)
Female
1501 (52.0)
1315 (52.3)
340 (52.4)
Race/ethnicity
White
828 (28.7)
1129 (44.9)
379 (58.4)
Black
981 (34.0)
528 (12.9)
72 (11.1)
Hispanic
733 (25.4)
533 (21.0)
110 (17.0)
Asian
346 (12.0)
325 (21.2)
88 (13.6)
Medical History
History of diabetes
395 (13.7)
312 (12.4)
54 (8.4)
Current smoker
373 (12.9)
338 (13.4)
66 (10.2)
Aspirin Use at Exam 1 (%)
579 (20.1)
512 (20.4)
126 (19.4)
Physical Exam
Body mass index, kg/m2
28.7 (5.7)
28.1 (5.4)
27.8 (5.1)
Systolic blood pressure, mmHg
127.5 (21.7)
126.0 (21.6)
124.8 (20.7)
Diastolic blood pressure, mmHg
72.3 (10.4)
71.5 (10.3)
71.2 (9.7)
Laboratory Measurements
HDL cholesterol, mg/dL
50.6 (14.7)
50.8 (14.9)
51.0 (14.4)
Triglycerides, mg/dL
131.3 (87.7)
134.9 (96.9)
133.9 (79.2)
Total cholesterol, mg/dL
193.5 (35.8)
194.6 (36.6)
195.2 (34.3)
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Table S3: Distribution of COMT rs4818 and rs4680 genotypes by race in MESA.
rs4818
rs4680
Race
GG
GC
CC
MAF (G)
HWE
AA
AG
GG
MAF (A)
HWE
LD r2
Overall
677
2635
3004
0.32
<0.01
1106
2928
2316
0.40
<0.001
0.31
White
406
1206
869
0.41
>0.05
655
1236
593
0.51
>0.05
0.72
Black
74
547
1018
0.21
>0.05
178
685
806
0.31
>0.05
0.12
Hispanic
109
555
764
0.27
>0.05
211
704
514
0.39
>0.05
0.24
Asian
88
327
353
0.33
>0.05
62
303
403
0.28
>0.05
0.19
Abbreviations: MAF = minor allele frequency; HWE = Hardy-Weinberg Equilibrium; LD = Linkage disequilibrium
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Table S4: Parameter estimates of COMT rs4818 and rs4680 (per G allele) association with baseline cardiometabolic risk factors.
All
White
Black
Hispanic
Asian
Risk Factor
Beta
SE
P
Beta
SE
P
Beta
SE
P
Beta
SE
P
Beta
SE
P
Fibrinogen,
rs4818
-3.65
1.35
0.007
-0.81
2.11
0.70
-2.29
3.03
0.45
-4.94
3.02
0.10
-9.70
3.06
0.002
mg/dL
rs4680
0.53
1.29
0.68
0.84
1.96
0.67
1.70
2.78
0.54
-1.43
2.89
0.62
0.54
3.31
0.87
CRP, mg/L
rs4818
-0.06
0.10
0.58
0.32
0.16
0.05
-0.19
0.33
0.58
-0.44
0.23
0.05
-0.31
0.20
0.12
rs4680
0.17
0.11
0.11
0.33
0.15
0.03
0.09
0.27
0.74
0.003
0.22
0.99
-0.01
0.27
0.97
ICAM, ng/mL
rs4818
-1.05
2.22
0.64
-2.86
2.93
0.33
10.52
7.85
0.18
-3.22
5.84
0.58
1.09
4.95
0.82
rs4680
-1.12
2.11
0.59
-1.20
2.77
0.66
3.83
6.92
0.58
-0.34
5.66
0.95
-3.97
4.91
0.42
IL-6, pg/mL
rs4818
-0.02
0.02
0.44
0.03
0.04
0.37
-0.01
0.06
0.91
-0.05
0.05
0.30
-0.09
0.05
0.08
rs4680
0.02
0.04
0.50
0.02
0.03
0.47
0.03
0.05
0.59
0.10
0.04
0.02
-0.10
0.06
0.13
SBP, mmHg
rs4818
-0.23
0.39
0.56
0.13
0.56
0.81
-0.12
0.93
0.90
-0.49
0.83
0.55
-1.28
1.08
0.24
rs4680
0.01
0.36
0.99
0.17
0.52
0.74
0.21
0.78
0.78
-0.45
0.76
0.55
-0.16
1.07
0.88
DBP, mmHg
rs4818
0.03
0.19
0.88
0.16
0.28
0.55
0.03
0.46
0.96
-0.25
0.38
0.52
0.06
0.52
0.91
rs4680
0.03
0.18
0.85
0.09
0.26
0.74
-0.03
0.37
0.94
-0.30
0.36
0.41
0.71
0.56
0.21
Hemoglobin
rs4818
-0.02
0.02
0.22
0.00
0.02
0.95
-0.07
0.05
0.15
-0.05
0.06
0.34
-0.07
0.04
0.12
A1c, %
rs4680
-0.02
0.01
0.20
-0.01
0.02
0.41
-0.01
0.04
0.86
-0.02
0.06
0.69
-0.08
0.05
0.12
Fasting
rs4818
-0.45
0.48
0.35
0.69
0.59
0.24
-3.36
1.34
0.01
-2.50
1.74
0.15
-2.36
1.39
0.09
glucose, mg/dl rs4680
-1.15
0.96
0.23
0.44
0.52
0.40
-1.69
1.21
0.16
-0.86
1.64
0.60
-3.86
1.65
0.02
Triglycerides,
rs4818
0.17
1.66
0.92
-1.57
4.38
0.72
-0.12
4.71
0.98
0.60
2.56
0.81
0.51
3.00
0.86
mg/dL
rs4680
-3.42
1.83
0.06
0.06
2.43
0.98
-4.14
3.33
0.21
-5.88
3.47
0.09
-8.52
4.90
0.08
HDL-C,
rs4818
0.03
0.26
0.89
-0.05
0.41
0.90
-0.07
0.64
0.91
0.42
0.51
0.42
-0.22
0.62
0.72
mg/dL
rs4680
0.33
0.24
0.17
-0.03
0.40
0.93
0.43
0.52
0.41
0.60
0.44
0.18
0.59
0.69
0.39
LDL-C, rs4818 0.08 0.63 0.90 0.75 0.92 0.42 -0.69 1.53 0.65 -0.79 1.37 0.56 0.10 1.55 0.95
mg/dL
rs4680
-0.14
0.58
0.81
0.13
0.86
0.88
-1.11
1.24
0.37
-0.74
1.27
0.56
1.79
1.76
0.31
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Table S5: COMT rs4818 and rs4680 gene dosage (per allele*) association with rates of CVD stratified by race and sex.
SNP
Females
Males
Race/Ethnicity
Events/N
HR 95% CI
P
Events/N
HR, 95% CI
P
rs4818
Overall
226/3271
0.93 [0.75-1.14]
0.48
298/2977
0.80 [0.67-0.97]
0.02
White
97/1300
1.04 [0.77-1.41]
0.80
117/1179
0.85 [0.65-1.11]
0.24
Black
55/846
0.77 [0.45-1.32]
0.34
75/729
0.87 [0.58-1.32]
0.52
Hispanic
54/736
0.75 [0.47-1.18]
0.21
83/690
0.67 [0.46-0.98]
0.04
Asian
20/389
0.94 [0.50-1.79]
0.86
23/379
0.83 [0.42-1.64]
0.59
rs4680
Overall
226/3271
0.95 [0.78-1.15]
0.59
298/2977
0.95 [0.79-1.14]
0.59
White
97/1300
1.14 [0.85-1.52]
0.38
117/1179
0.95 [0.73-1.22]
0.68
Black
55/846
0.88 [0.61-1.29]
0.52
75/729
1.04 [0.72-1.48]
0.84
Hispanic
54/736
0.75 [0.51-1.11]
0.15
83/690
1.04 [0.76-1.43]
0.79
Asian
20/389
0.89 [0.43-1.81]
0.74
23/379
0.55 [0.30-1.03]
0.06
Abbreviations: HR = Hazard ratio
* Allele key: rs4818 coded allele = G; rs4680 coded allele = G
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Table S6: Hormone replacement therapy (HRT) use among women assessed at Exam 1 and rates of CVD by COMT rs4818 and rs4680 genotype
stratified by HRT use and race.
Random effects meta-analysis of HRT ever and never use. I2 for rs4818 HRT no = 65.1; HRT yes = 0. I2 for rs4680 HRT no = 72.7; HRT yes = 0
Hormone replacement therapy (HRT) use ever
SNP
Race/ethnicity
Total (%)
CC
GC
GG
HRT ever no*
HRT ever yes*
P
interaction
rs4818
Overall
1540 (51.1)
708 (49.6)
647 (51.2)
185 (57.6)
1.22 [0.74-2.02], 0.44
0.64 [0.45-0.89], 0.009
0.047
White
772 (64.1)
269 (64.7)
367 (62.2)
136 (68.3)
2.20 [1.34-3.07], 0.002
0.59 [0.39-0.89], 0.01
0.02
Black
384 (47.4)
241 (48.5)
127 (45.0)
16 (50.0)
0.94 [0.49-1.78], 0.84
0.96 [0.41-2.30], 0.94
0.97
Hispanic
268 (40.6)
144 (39.9)
107 (42.3)
17 (37.0)
0.83 [0.51-1.34], 0.44
0.62 [0.17-1.31], 0.46
0.39
Asian
116 (34.2)
54 (34.8)
46 (32.9)
16 (36.4)
1.28 [0.53-3.07], 0.58
0.59 [0.22-1.58], 0.30
0.84
met/met
val/met
val/val
rs4680
Overall
1701 (55.4)
296 (57.7)
723 (51.8)
521 (47.1)
1.14 [0.66-1.95], 0.64
0.75 [0.56-1.02], 0.07
0.26
White
772 (64.1)
205 (66.8)
381 (63.0)
186 (62.5)
2.39 [1.42-4.01], 0.001
0.72 [0.49-1.04], 0.08
2E-04
Black
419 (50.9)
45 (50.6)
158 (47.9)
181 (46.2)
0.93 [0.57-1.53], 0.78
0.96 [0.47-1.95], 0.91
0.43
Hispanic
302 (45.1)
39 (41.5)
138 (40.8)
91 (39.9)
0.83 [0.54-1.28], 0.40
0.59 [0.22-1.61], 0.31
0.26
Asian
137 (39.6)
7 (30.4)
46 (37.4)
63 (32.6)
0.81 [0.30-2.19], 0.68
0.88 [0.30-2.61], 0.82
0.24
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Table S7: Aspirin user (%) > 3 days/week by COMT rs4818 genotype at the five MESA exams.
rs4818 genotype
Exam
CC
GC
GG
1
577 (20.0)
511 (20.3)
125 (19.3)
2
863 (31.6)
762 (31.4)
185 (29.2)
3
886 (33.9)
799 (34.6)
195 (32.3)
4
944 (37.2)
824 (36.4)
216 (36.0)
5
905 (45.2)
825 (44.4)
215 (44.4)
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Supplementary Table S8: COMT rs4818 and rs4680 gene dosage (per allele*) association with rates of CVD stratified by time-varying aspirin
and HRT ever use among white women.
SNP
Aspirin
No HRT
HR [95% CI], P
Ever HRT
HR [95% CI], P
rs4818
<3 days/week
3.13 [1.53-6.39], 0.002
0.34 [0.16-0.69], 0.004
>3 days/week
1.99 [0.90-4.40], 0.09
0.80 [0.42-1.52], 0.49
P
interaction
0.39
0.08
rs4680
<3 days/week
3.02 [1.38-6.58], 0.006
0.46 [0.25-0.85], 0.01
>3 days/week
2.25 [0.97-5.24], 0.06
1.27 [0.69-2.35], 0.45
P
interaction
0.613
0.02
* Allele key: rs4818 coded allele = G; rs4680 coded allele = G
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Aims: Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. Methods: We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. Results: COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (β=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05). Conclusions: COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.
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Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima-media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive uses of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events. Participants were from the Multi-Ethnic Study of Atherosclerosis (MESA). Predictive values of carotid plaque, IMT, and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6779 participants were mean (SD) 62.2 (10.2) years old; 49.9% had CAC, and 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex, and race) alone did not predict events. Compared with traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased the most by the addition of CAC presence (CVD, 0.776; CHD, 0.784; P<0.001) followed by carotid plaque presence (CVD, c=0.760; CHD, c=0.757; P<0.05). Compared with risk factors (c=0.782), carotid plaque presence (c=0.787; P=0.045) but not CAC (c=0.785; P=0.438) improved prediction of stroke/transient ischemic attacks. In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/transient ischemic attack event prediction. © 2015 American Heart Association, Inc.
Article
Objective: Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and results: We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar. Conclusions: Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.