Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study.

Abstract

Carotid intima-media thickness (IMT) is a quantitative measure of subclinical atherosclerosis that is predictive of subsequent myocardial infarction and stroke. There is controversy regarding the proportion of variability in IMT explained by genetic factors. Thus, it is uncertain whether carotid IMT is a heritable trait that can be used in genetic studies.
From 1996 to 1998, we measured carotid IMT in 906 men (mean age, 56.7 years) and 980 women (mean age, 57.4 years) from 586 extended families (1630 sib pairs) in the Framingham Offspring cohort. B-mode carotid ultrasonography was used to define mean and maximum IMT of the common carotid artery (CCA) and internal carotid artery (ICA). Correlation coefficients were calculated in pairs of siblings. Variance component methods were used to estimate heritability with crude, age- and sex-adjusted, and multivariable-adjusted normalized deviates.
Multivariable-adjusted correlation coefficients for mean CCA and ICA IMT were 0.16 and 0.16, respectively. Crude, age- and sex-adjusted, and multivariable-adjusted heritabilities were 0.67, 0.44, and 0.38 for the mean CCA IMT (all P<0.001) and 0.43, 0.37, and 0.35 for the mean ICA IMT (all P<0.001). For CCA IMT, 27% of the overall variance was due to measured covariates; 38% was due to heritable factors.
These data suggest that a substantial proportion of the variability in carotid IMT is explained by genetic factors. Further studies of genetic linkage and candidate gene association are warranted to identify specific genetic variants predisposing to subclinical atherosclerosis and stroke.

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D'Agostino and Christopher J. O'Donnell
Caroline S. Fox, Joseph F. Polak, Irmarie Chazaro, Adrienne Cupples, Philip A. Wolf, Ralph A.
StudyWomen : Heritability of Carotid Intima-Media Thickness in the Framingham Heart
Genetic and Environmental Contributions to Atherosclerosis Phenotypes in Men and
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright © 2003 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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doi: 10.1161/01.STR.0000048214.56981.6F
2003;34:397-401; originally published online January 30, 2003;
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Genetic and Environmental Contributions to Atherosclerosis
Phenotypes in Men and Women
Heritability of Carotid Intima-Media Thickness in the Framingham Heart Study
Caroline S. Fox, MD, MPH; Joseph F. Polak, MD, MPH; Irmarie Chazaro, MA; Adrienne Cupples, PhD;
Philip A. Wolf, MD; Ralph A. D’Agostino, PhD; Christopher J. O’Donnell, MD, MPH
Background and Purpose—Carotid intima-media thickness (IMT) is a quantitative measure of subclinical atherosclerosis
that is predictive of subsequent myocardial infarction and stroke. There is controversy regarding the proportion of
variability in IMT explained by genetic factors. Thus, it is uncertain whether carotid IMT is a heritable trait that can be
used in genetic studies.
Methods—From 1996 to 1998, we measured carotid IMT in 906 men (mean age, 56.7 years) and 980 women (mean age,
57.4 years) from 586 extended families (1630 sib pairs) in the Framingham Offspring cohort. B-mode carotid
ultrasonography was used to define mean and maximum IMT of the common carotid artery (CCA) and internal carotid
artery (ICA). Correlation coefficients were calculated in pairs of siblings. Variance component methods were used to
estimate heritability with crude, age- and sex-adjusted, and multivariable-adjusted normalized deviates.
Results—Multivariable-adjusted correlation coefficients for mean CCA and ICA IMT were 0.16 and 0.16, respectively.
Crude, age- and sex-adjusted, and multivariable-adjusted heritabilities were 0.67, 0.44, and 0.38 for the mean CCA IMT
(all P?0.001) and 0.43, 0.37, and 0.35 for the mean ICA IMT (all P?0.001). For CCA IMT, 27% of the overall variance
was due to measured covariates; 38% was due to heritable factors.
Conclusions—These data suggest that a substantial proportion of the variability in carotid IMT is explained by genetic
factors. Further studies of genetic linkage and candidate gene association are warranted to identify specific genetic
variants predisposing to subclinical atherosclerosis and stroke. (Stroke. 2003;34:397-401.)
Key Words: epidemiology ? genetics ? intima-media thickness
G
atherosclerosis have been shown to be similar to traditional
risk factors for clinical cardiovascular disease.2Carotid
intima-media thickness (IMT) is a measure of subclinical
atherosclerosis that is correlated with traditional coronary
heart disease risk factors3–6and coronary atherosclerotic
burden7,8and is predictive of subsequent myocardial infarc-
tion and stroke.9,10It has been suggested that thickening of
the common carotid artery (CCA) intima might be more
representative of total body atherosclerotic burden, whereas
thickening of the internal carotid artery (ICA) IMT might
represent focal atherosclerotic plaques.8
Carotid IMT has also been shown to be associated with a
family history of cardiovascular disease.11Evidence from a
single study of families of Mexican descent suggests that
carotid IMT is heritable, with estimates ranging from 0.86 to
0.92.12However, these very high heritability estimates have
enetic and environmental factors have been linked to the
cause of atherosclerosis.1Risk factors for subclinical
not been reproduced in other populations. Determining
whether carotid IMT is heritable in a general population of
men and women would suggest that this noninvasive quanti-
tative measure of vascular disease might be of great utility for
subsequent use in genetic studies. Furthermore, possible
differences in the pathophysiology of CCA and ICA IMT
might allow the exploration of differential gene regulation in
specific vascular beds. Thus, we hypothesized that carotid
IMT is a heritable phenotype, and we sought to test this
hypothesis in the Framingham Heart Study Offspring cohort.
Methods
Study Population
This investigation comprised subjects from the Framingham Off-
spring Study who were undergoing B-mode carotid ultrasonography
during examination cycle 6 (1996 to 1998). We measured carotid
IMT in 906 men and 980 women from 586 extended families with
1630 sib pairs.
Received May 22, 2002; final revision received August 7, 2002; accepted August 21, 2002.
From the National Heart, Lung and Blood Institute’s Framingham Heart Study (C.S.F., P.A.W., R.A.D., C.J.O.), Framingham, Mass; Cardiology
Division (C.J.O.), Department of Medicine, Massachusetts General Hospital, Boston; Departments of Radiology (J.F.P.) and Medicine (C.S.F.), Brigham
and Women’s Hospital, Harvard Medical School, Boston, Mass; Departments of Neurology and Preventive Medicine and Epidemiology (P.A.W.), Boston
University School of Medicine, Boston, Mass; Department of Biostatistics and Epidemiology (I.C., L.A.C.), Boston University, Boston, Mass; and
National Heart, Lung, and Blood Institute, National Institutes of Health (C.J.O.), Bethesda, Md.
Correspondence to Christopher J. O’Donnell, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702. E-mail chris@fram.nhlbi.nih.gov
© 2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.orgDOI: 10.1161/01.STR.0000048214.56981.6F
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The Framingham Heart Study began in 1948 with the enrollment
of 5209 men and women 28 to 62 years of age, with subjects
undergoing examinations every 2 years.13,14In 1971, 5124 men and
women were enrolled in the Framingham Heart Study Offspring
cohort, which included the children or spouses of the children of the
original cohort. Offspring subjects underwent examinations approx-
imately every 4 years; the design and methodology have been
previously described.15,16
For this particular study, of the total 5124 subjects who attended
the initial offspring examination, 3532 attended cycle 6. Of these,
154 did not undergo carotid ultrasound, 1066 were excluded because
they were not part of a biological family, and 426 were further
excluded because they were not part of a biological family whose
members had carotid ultrasound data. Thus, a total of 1886 subjects
made up the study population.
Assessment of Risk Factors and
Cardiovascular Disease
Details regarding the methods of risk factor measurement and
laboratory analysis have been given elsewhere.17Each examination
included a cardiovascular disease assessment, 12-lead ECG, and
blood testing. Measured covariates for the present study were
assessed at the time of carotid ultrasonography. Subjects with a
fasting glucose level ?140 mg/dL, with a random nonfasting glucose
level ?200 mg/dL, and/or on treatment for diabetes were defined as
diabetic. Subjects with a systolic blood pressure ?140 mm Hg, with
a diastolic blood pressure ?90 mm Hg (average of 2 readings taken
by the examining physician), and/or on antihypertensive medication
were defined as hypertensive. Fasting cholesterol measures included
total cholesterol, high-density lipoprotein (LDL) cholesterol, and
triglycerides. Smoking status was defined as number of cigarettes
smoked per day in the year preceding the examination. Body mass
index was defined as weight (kilograms) divided by the square of
height (meters). Fatal and nonfatal cardiovascular outcomes were
monitored by clinic examinations, hospital surveillance, and com-
munication with participants who did not attend a clinic examination.
A panel of 3 experienced investigators reviewed and adjudicated the
occurrence of all incident cardiovascular events.
Carotid IMT Assessment
Subjects underwent ultrasonography according to standard protocol.
Imaging was conducted with a Toshiba SSH-140A imaging unit that
used a high-resolution, 7.5-MHz transducer for the CCA and a
5.0-MHz transducer for the ICA. Images were gated to an ECG;
end-diastolic images were acquired.
The following images were obtained from the right and left sides:
2 longitudinal images of the distal CCA, 1 at end diastole and 1 at
end systole, and 2 longitudinal views of the ICA at end diastole.
Measurement of the peak systolic velocity in the ICA was obtained
with color Doppler imaging and duplex ultrasound. Measurements
were made by a single trained sonographer blinded to all clinical
information and overread by 1 of the investigators (J.F.P.). Based on
25 readings by 2 separate readers, correlation coefficients for the
mean and maximum ICAs were 0.83 and 0.84, respectively. This is
comparable to previously reported results with similar techniques.18
All studies were recorded on optical disk and read according to a
standardized protocol. The high-resolution images of the CCA and
ICA were analyzed to calculate near- and far-wall IMT, lumen
diameter, and vessel width at each arterial site. All measurements of
lumen and wall thickness were calculated with a specially designed
computer program.8,9
To quantify the degree of thickening of the carotid artery walls,
IMT measures were summarized into 2 variables: 1 for CCA and 1
for ICA. Mean and maximum wall thicknesses of the CCA and ICA
were defined as the mean of the wall thickness or the mean of the
maximum wall thickness for the near and far walls on the left and
right sides. The number of available measurements for averaging
ranged from 1 to 4 for the CCA and from 1 to 8 for the ICA.
Statistical Analysis
Phenotypes of interest included mean and maximum IMT measures
of the CCA and ICA. If either side was missing, we used the
available measure at 1 side. Statistical analyses were conducted with
SAS version 6.1219and SOLAR.20Subjects were contained in
sibships (of a total of 657 sibships) with the following distributions:
62% had 2 members, 24% had 3 members, 10% had 4 members, and
4% had ?5 members. There were 1630 sibling pairs: 378 male-male,
825 male-female, and 427 female-female pairs. Descriptive statistics
using means, medians, and SD were performed on all variables when
appropriate.
We calculated crude, age- and sex-adjusted, and multivariable-
adjusted normalized deviates. For these adjustments, we used mul-
tiple linear regression separately for men and women. Covariates
(continuous measures except when otherwise specified) in the
multivariable models included age, systolic blood pressure, ciga-
rettes smoked per day, total cholesterol, HDL cholesterol, log
triglycerides, diabetes status (yes/no), body mass index, antihyper-
tensive treatment (yes/no), and menopausal status (yes/no) and
hormone replacement therapy in women (yes/no). From these re-
gression models, we used standardized residuals. Because these
residuals were skewed and the variance component method is
sensitive to the assumption of normality, we obtained normalized
deviates from the rank of the residuals.
We calculated heritability in 2 ways. First, we used FCOR in
SAGE to calculate the intraclass correlations for sibling pairs.21An
estimate of heritability is obtained by doubling the sib pair correla-
tion.22In addition, the variance component model implemented in
SOLAR was used to calculate heritabilities from the normalized
deviates. Similarly, we obtained estimates of heritability for men and
women separately from normalized deviates.
Heritability measurements estimate the proportion of variability in
the measure attributable to the additive effect of genes and represent
the contribution of both genes and early common environment. The
underlying model assumes that variation in the trait can be parti-
tioned into genetic, known covariates, and environmental compo-
nents. It is assumed that the genetic component is polygenic with no
variation attributable to dominance components. To determine the
portion of variation resulting from measured covariates, we used a
regression model with men and women combined.
Results
Baseline Characteristics
Baseline characteristics of our study sample are shown in
Table 1. The mean age was 56.7 years for men and 57.4 years
for women. We found that 40% of men and 36% of women
TABLE 1.Baseline Characteristics of Study Subjects
Men, n?906,
Mean (SD)
Women, n?980,
Mean (SD)
Age, y
Systolic blood pressure, mm Hg
Total cholesterol, mmol/L
Triglycerides, mmol/L
HDL cholesterol, mmol/L
Body mass index, kg/m2
Current smoking, %
Postmenopause
Hormone replacement therapy, %
Prevalent hypertension, %
Hypertension treatment, %
Diabetes, %
Cardiovascular disease, %
56.7 (9.7)
128.0 (16.3)
5.2 (1.1)
1.4 (0.02)
1.1 (0.3)
28.5 (4.4)
16.8
N/A
N/A
40
27
5.6
13
57.4 (10.1)
125.4 (19.7)
5.5 (1.0)
1.3 (0.02)
1.5 (0.4)
27.6 (6.2)
15.3
74
23
36
24
4.4
8
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were hypertensive, 6% of men and 4% of women were
diabetic, and 13% of men and 8% of women had cardiovas-
cular disease. Mean and maximum values of CCA and ICA
IMT are shown in Table 2.
Pearson’s correlation coefficient data between covariates
and measures of IMT are shown in Table 3. Age, systolic
blood pressure, triglycerides, cigarette smoking, and body
mass index were all significantly correlated with measures of
IMT; HDL cholesterol was inversely correlated with IMT.
Mean IMT measures were significantly higher in diabetics
(P?0.001) and in individuals with cardiovascular disease
(P?0.001).
Correlation Coefficients and Heritability Estimates
For mean and maximum CCA and ICA IMT, correlation
coefficients for sibling:sibling pairs were calculated with
SAGE FCOR. The correlation coefficients are shown in
Table 4. In crude, age- and sex- adjusted, and multivariable
adjusted analyses giving equal weights to pedigrees, the
correlation coefficients for mean CCA IMT were 0.36, 0.20,
and 0.16, respectively. For mean ICA IMT, the correlation
coefficients were 0.25, 0.18, and 0.16, respectively. The
maximum and mean results were similar for CCA and ICA,
respectively. The adjusted correlation coefficients can be
used to calculate simple estimates of heritability with the
equation h2?2r (h2indicates heritability and r is sibling pair
correlations). When the multivariable-adjusted sibling:sibling
correlation coefficients in Table 4 are used, the estimates of h2
for mean CCA and mean ICA were 0.32 and 0.32,
respectively.
Heritability estimates derived from SOLAR are presented
in Table 5. Heritability indicates the proportion of variance in
IMT attributed to the additive effect of genes and early
common environment. Heritability estimates were derived
from normalized deviates of crude, age- plus sex-, and age-,
sex-, plus multivariable-adjusted residuals. The age-, sex-
plus multivariable-adjusted heritabilities were as follows:
mean CCA,0.38(P?0.001);
(P?0.001); mean ICA, 0.35 (P?0.001); and maximum ICA,
0.31 (P?0.001). Therefore, 38% of the interindividual vari-
ability in mean CCA is attributable to the effect of genes. The
results were similar when subjects with prevalent cardiovas-
cular disease were excluded from the analyses (data not
shown). Sex-specific heritabilities were also calculated.
Among men, the ICA IMT heritabilities were slightly higher
than in the pooled analyses, whereas among women, the CCA
IMT heritabilities were slightly higher; however, these dif-
ferences were not significant (data not shown).
maximum CCA, 0.39
Components of Variance Analysis
The overall contribution of genetic factors and measured
covariates to carotid IMT was examined. The contribution of
genetic factors to overall variation in mean CCA was 38%
(heritability), and the contribution of measured covariates to
overall variation was 27%, leaving a residual of 35%. The
contribution of genetic factors to the overall variation in mean
ICA was 35% (heritability), and the contribution of measured
covariates was 18%, leaving a residual of 47%. Results for
the maximum CCA and maximum ICA were similar.
Discussion
We have found that both mean and maximum measurements
of CCA and ICA IMT are heritable. Heritability estimates
using correlation coefficients and variance components meth-
ods are similar, and the magnitude of heritabilities for carotid
IMT is similar to those reported for other quantitative
cardiovascular traits such as systolic blood pressure and
serum cholesterol. These data suggest that a substantial
TABLE 3. Correlation of Carotid Artery IMT with Covariates
CCA
Mean
CCA
Maximum
ICA
Mean
ICA
Maximum
Age
Systolic blood pressure
Total cholesterol
HDL cholesterol
Triglycerides
Cigarettes/day
Body mass index
0.42‡
0.31‡
0.02
?0.19‡
0.14‡
0.06†
0.13‡
0.42‡
0.31‡
0.02
?0.20‡
0.14‡
0.07
0.14‡
0.31‡
0.23‡
0.02
?0.18‡
0.15‡
0.10‡
0.14‡
0.32‡
0.23‡
0.02
?0.17‡
0.15‡
0.10‡
0.13‡
‡P value?0.001.
TABLE 2.CCA and ICA IMT Measures
Men,
mean (SD)
Women,
Mean (SD)
CCA mean, mm
CCA maximum, mm
ICA mean, mm
ICA maximum, mm
0.62 (0.17)
0.75 (0.19)
0.64 (0.42)
0.87 (0.55)
0.60 (0.12)
0.69 (0.15)
0.52 (0.34)
0.72 (0.47)
TABLE 4.
IMT Using SAGE FCOR
Sibling?Sibling Correlation Coefficients for Carotid
CCA
Mean
CCA
maximum
ICA
mean
ICA
Maximum
Crude
Age-, sex-adjusted
Multivariable-adjusted*
0.36
0.20
0.16
0.36
0.21
0.17
0.25
0.18
0.16
0.21
0.16
0.14
*Includes adjustment for age, sex, systolic blood pressure, number of
cigarettes/day, total cholesterol, HDL cholesterol, triglycerides, diabetes status,
body mass index, antihypertensive treatment, menopausal status, and hormone
replacement therapy.
TABLE 5.
Mean (SE)
Estimated Variance Components Heritabilities,
CCA
Mean
CCA
Maximum
ICA
Mean
ICA
Maximum
Crude
Age-, sex-adjusted
Multivariable-adjusted*
0.67 (0.06)
0.44 (0.06)
0.38 (0.06)
0.66 (0.06)
0.45 (0.06)
0.39 (0.06)
0.43 (0.06)
0.37 (0.06)
0.35 (0.06)
0.36 (0.06)
0.33 (0.06)
0.31 (0.06)
All P values?0.0001.
*Includes adjustment for age, sex, systolic blood pressure, number of
cigarettes/day, total cholesterol, HDL cholesterol, triglycerides, diabetes status,
body mass index, anti-hypertensive treatment, menopausal status, and hor-
mone replacement therapy.
Fox et alHeritability of Carotid Intima-Media Thickness
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proportion of the variability in carotid IMT is explained by
genetic factors.
Carotid IMT is a marker of subclinical cardiovascular
disease that has been shown to be associated with traditional
coronary heart disease risk factors3–6and coronary athero-
sclerotic burden7,8and to be predictive of subsequent cardio-
vascular events.9,10Multiple prior studies have demonstrated
the contribution of genetic factors to individual coronary
heart disease risk factors, including systolic blood pressure,23
HDL cholesterol,24and diabetes mellitus.25A large study of
21 000 twins demonstrated an increased risk of premature
coronary heart disease among monozygotic and dizygotic
twins,26but there is a paucity of population-based genetic
epidemiologic studies linking myocardial infarction or the
underlying condition of atherosclerosis to genetic factors.
Thus, our findings represent the first report of a large,
population-based heritability analysis of carotid IMT.
Although prior studies have examined the association of
specific genetic variants with carotid IMT, it has not been
definitively demonstrated that carotid IMT is heritable. In a
sample drawn from 1742 residents of Mexico City, CCA IMT
and ICA IMT were highly heritable, with estimates of 0.92
for CCA and 0.86 for ICA after adjustment for covariates;
however, the number of sibships studied (n?46) was small.12
Our finding of consistent evidence of heritability of the CCA
and ICA IMT in our large, well-characterized population
reinforces the validity of these prior findings and extends
them to a large white cohort.
It has been suggested that CCA IMT might represent
diffuse wall thickening resulting from smooth muscle accu-
mulation and matrix deposition, whereas ICA IMT might be
more prone to focal atherosclerotic plaques,8possibly related
to endothelial dysfunction and hemodynamic flow in the
ICA.4,27Indeed, thickening of the ICA intima has been shown
to be somewhat more strongly associated with an increased
risk of incident disease than in the CCA.8,28Arterial bifurca-
tions are lesion-prone areas that have increased activity of
thrombosis, lipid deposition, and atherosclerosis,29thought to
be a direct result of hemodynamic factors.30,31In vitro
experimental models have demonstrated that atherosclerotic
plaques are most often formed along bifurcations and along
the inner wall of curvatures.32,33
In contrast, the CCA is exposed primarily to laminar blood
flow, and in in vivo experiments, CCA intimal thickness has
been shown to be inversely related to wall shear stress,
independent of age, blood pressure, body mass index, and
diabetes mellitus.34–37Low wall shear stress is hypothesized
to increase the duration of time that blood comes into contact
with the endothelial wall, enhancing atherogenic particle
delivery and vessel wall adherence.27,35Our finding of heri-
tability in the CCA and ICA IMT suggests that both processes
might be examined through carotid artery imaging and that
the hypothesized pathophysiological differences in CCA and
ICA IMT might be attributable to different sets of genes.
Because carotid IMT is a quantitative, intermediate pheno-
type for clinical atherosclerosis, it may be a useful interme-
diate phenotype for genetic studies. There is a growing body
of evidence for associations between carotid IMT or related
carotid phenotypes, but the genes implicated in carotid IMT
variability remain undefined. Genes in several pathways
implicated in the pathogenesis of atherosclerosis have been
considered. Some studies have yielded suggestive results for
the T/T genotype of the b-fibrinogen gene,38factor V Lei-
den,39the D/D genotype of the angiotensin-converting en-
zyme insertion/deletion polymorphism,40and the paraxonase
gene,38whereas others have not found a relationship.31,41–44
In our analysis, heritability was only modestly attenuated by
adjustment for known cardiac risk factors, suggesting that
genes implicated in the variability of these phenotypes may
not be major contributors to carotid IMT.
Certain limitations of our study deserve attention. The
predominantly white population that makes up most of the
Framingham Offspring cohort may limit the generalizability
of our findings. Significant differences in the prevalence of
genes important to heritability and different magnitudes
of genes by environment effects may lead to estimates of
heritability that differ among ethnic groups. However, coro-
nary heart disease risk factor relationships from Framingham
have been validated in 6 ethnically and geographically
diverse cohorts and were found to be applicable in other
populations, reinforcing the representativeness of our data.45
Second, in ?25% of our ICA measurements, we were able to
assess only the right or the left ICA but not both. In a
subanalysis restricted to those with both right and left ICA
measurements present, heritability measurements were actu-
ally higher, reflecting lower measurement error in the com-
bined ICA measure. Last, we used CCA and ICA IMT as a
marker of subclinical atherosclerosis. However, CCA and
ICA IMT may not reflect similar atherosclerotic processes,
and these hypothesized pathophysiological differences may
lead to the eventual discovery of specific genes that are
responsible for causing region-specific atherosclerosis.
In conclusion, a substantial proportion of the variability in
carotid IMT is explained by genetic factors. Further studies of
genetic linkage and candidate gene association are warranted
to identify the specific genetic variants associated with this
marker of increased risk for atherosclerosis and stroke.
Acknowledgments
This work was supported by the National Heart, Lung and Blood
Institute’s Framingham Heart Study (N01-HC-25195), National
Institute of Neurological Disorders and Stroke (NIH/NINDS 5R01-
NS17950-20), and Framingham Heart Study Visiting Scientist Pro-
gram, which is supported by Servier Amerique.
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