From the Division of Epidemiology, School of Public Health (A.R.F.,
P.G.M.) and Department of Laboratory Medicine and Pathology (M.Y.T., J.H.E.),
University of Minnesota, Minneapolis; Department of Epidemiology, School of
Hygiene and Public Health (F.J.N.), Johns Hopkins University, Baltimore, Md;
Laboratory of Cardiovascular Diseases, Oregon Regional Primate Research Center
(M.R.M., D.L.H.), Beaverton, Ore; and Collaborative Studies Coordinating
Center (C.E.D.), Chapel Hill, NC.
Methods and Results—We used a prospective case-cohort design to
determine whether tHcy-related factors are associated with incidence of
CHD over an average of 3.3 years of follow-up in a biracial sample of
middle-aged men and women. Age-, race-, and field center–adjusted CHD
incidence was associated positively (P<0.05) with tHcy
in women but not men, and CHD was associated negatively
(P<0.05) with plasma folate (women only), plasma
pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women
only). However, after accounting for other risk factors, only plasma
pyridoxal 5'-phosphate was associated with CHD incidence; the relative
risk for the highest versus lowest quintile of pyridoxal 5'-phosphate
was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the
C677T mutation of the
methylenetetrahydrofolate reductase
gene or with 3 mutations of the cystathionine ß-synthase gene.
Conclusions—Our prospective findings add uncertainty to
conclusions derived mostly from cross-sectional studies that tHcy is a
major, independent, causative risk factor for CHD. Our findings point
more strongly to the possibility that vitamin B6 offers
independent protection. Randomized trials, some of which are under way,
are needed to better clarify the interrelationships of tHcy, B
vitamins, and cardiovascular disease.
Heterozygous CBS deficiency, homozygosity for
the thermolabile variant of MTHFR, and low dietary folate,
vitamin B12, or vitamin B6
(PLP) are among the factors that can elevate tHcy
concentrations.1 Prospective evidence relating
these factors to incident CHD is limited.7 9 10 11
Two prospective epidemiological studies reported low dietary folate and
B611 or low serum
folate9 to be associated significantly with
increased incidence of CHD. Another study7 found
low serum folate and vitamin B6 associated,
although not statistically significantly, with increased CHD incidence.
This latter study also found the C677T mutation
of the MTHFR gene was not associated with CHD
incidence.10
To provide additional prospective evidence on these topics, we used a
nested case-cohort design within the ARIC study to determine the
association of fasting serum tHcy with CHD incidence. In addition, we
assessed the contributions to CHD of dietary and plasma
B12, PLP, and folate, as well as several genetic
variants associated with tHcy concentration.
Baseline Measurements
Trained interviewers collected information on usual alcohol intake and
on dietary intake using an adaptation of Willett's food frequency
questionnaire.17 Interviewers asked about use of
vitamin supplements in a medication interview. Because we did not
obtain dose and frequency of vitamin supplementation, we coded vitamin
supplement use as "any" versus "none" for analysis.
ARIC measured fasting plasma total
cholesterol,18
triglycerides,19 HDL
cholesterol,20 and
fibrinogen21 and calculated LDL
cholesterol.22 We defined diabetes as
fasting glucose
Ascertainment and Classification of Incident CHD Cases
Cohort Sample
Processing of Stored Baseline Samples
Laboratory Measurements
We determined the presence or absence of the
T833C and G919A mutations
and the 68-bp insertion of the CBS
gene.28 29 To determine the
C677T mutation of the MTHFR gene, we
used the method of Rozen and associates.30
Data Analysis
To determine the relation of tHcy with other variables, some of
which may be confounders in this analysis, we categorized the
cohort sample into fifths based on quintile cutpoints and used ANCOVA
to compute age-, race-, and sex-adjusted mean levels or percentages of
the other variables for each quintile. We also computed weighted
correlations among pairs of vitamin variables or tHcy.
To test study hypotheses, we first used ANCOVA to compute age-, race-,
and sex-adjusted geometric mean or percentage values of study
variables for CHD cases versus the cohort after appropriate
weighting for the stratified case-cohort sampling design. We used
geometric means because tHcy and vitamin variables were right
skewed.
We computed relative risks and 95% CIs of CHD in relation to
categories of study variables using a weighted proportional hazards
regression, accounting for the stratified random sampling and the
case-cohort design by Barlow's method.32 We
tested for trend in relative risks across quintiles (coded 1 to 5)
using a
Correlates of tHcy
We detected no homozygotes or heterozygotes for the
G919A mutation of the CBS gene and
only 3 heterozygotes for the T833C mutation (1
case, 2 noncases). There was no association between prevalence of the
CBS insertion and tHcy (Table 1
Mean Differences Between CHD Cases and Noncases
Relative Risks of CHD
The C677T MTHFR mutation and the
CBS insertion were not associated with CHD incidence. For
example, adjusted for age, race, and center, the relative risks for
heterozygosity and homozygosity for the C677T
mutation of the MTHFR gene were 1.48 and 0.59, respectively,
in women and 1.33 and 0.84 in men (all P>0.10). The
relative risks for heterozygosity and homozygosity for the
CBS insertion mutation were 1.85 and 1.83, respectively, in
women and 1.01 and 0.26 in men (all P>0.05).
Although the simpler regression models suggested potential differences
in associations by sex (Table 3
In contrast with the cross-sectional studies, a majority of prospective
epidemiological studies of subjects initially free of CHD, published
either in full2 3 4 5 6 7 8 or in
abstract,37 38 do not show an association of tHcy
and CHD incidence. This suggests that elevated tHcy may be a
consequence, not a cause, of CHD.6 Recent
evidence suggests that endothelial dysfunction may
raise plasma tHcy.39 In patients with CHD,
elevated tHcy strongly predicts a poor outcome,40
further suggesting that it reflects the severity of CHD and possibly
the risk of thrombosis.
Plasma PLP, B12, and folate, which are cofactors
in homocysteine metabolism, were moderately strong
correlates of tHcy, as has been documented
previously.1 34 35 41 42 43 We found moderately
strong inverse associations of CHD with plasma PLP, folate, and vitamin
B12 in women and with PLP in men. However, in
multivariate analysis pooling men and women,
only PLP remained independently associated with CHD. Previous evidence
is not entirely consistent but suggests folate and PLP but not
vitamin B12 concentrations in the blood are
associated negatively with CHD
occurrence.7 9 34 35 41 42 43 Only 2 of these
previous studies7 9 were prospective. Vitamin
B6 deficiency can cause
atherosclerosis in animal models, and other possible
mechanisms of how vitamin B6 might protect
against CHD have been hypothesized.44
In contrast with a recent large study,11 we found
no significant association between questionnaire assessments of B
vitamins from food and CHD incidence. On the other hand, we found that
vitamin supplement use was associated with reduced risk of CHD in the
age-, race-, and field center–adjusted model for women. Users of
vitamin supplements had higher plasma B-vitamin concentrations than
nonusers, suggesting that vitamin supplementation contributed
to the inverse association between plasma PLP and CHD.
Despite the fact that MTHFRC677T
homozygosity was associated with higher tHcy levels, we found no
association of MTHFRC677T with CHD
incidence. Most recent reports,10 45 46 47 but not
all,48 49 50 have also found no association of
MTHFRC677T with CHD. The
T833C and G919A mutations
of the CBS gene together account for
Our prospective findings add uncertainty to conclusions derived mostly
from cross-sectional studies that tHcy is a major, independent,
causative risk factor for CHD. Our findings point more strongly to the
possibility that vitamin B6 offers independent
protection. Randomized trials, some of which are under way, are needed
to better clarify the interrelationships of tHcy, B vitamins, and
cardiovascular disease.
Received December 15, 1997;
revision received March 17, 1998;
accepted April 20, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins
The Atherosclerosis Risk in Communities (ARIC) Study
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Elevated plasma total
homocysteine (tHcy), low B-vitamin intake, and genetic
polymorphisms related to tHcy metabolism may play roles
in coronary heart disease (CHD). More prospective studies
are needed.
Key Words: : coronary disease • vitamins • homocysteine • polymorphism (genetics)
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Homocystinuria is a
rare autosomal recessive deficiency of CBS associated with an elevated
blood tHcy concentration and a very high incidence of premature
vascular disease. Moderately elevated tHcy also is believed to be a
risk factor for CHD, atherothrombotic stroke, and
peripheral vascular disease. A recent
meta-analysis1 estimated that each
5-µmol/L tHcy increase is associated with a 60% (men) to 80%
(women) greater risk of CHD. Although this evidence is compelling, only
two2 3 of five2 3 4 5 6
published prospective studies have found tHcy concentration to be a CHD
risk factor. One of these studies,2 when extended
by 2.5 years, no longer showed a statistically significant association
between tHcy and CHD incidence,7 nor did it
subsequently find a relation between tHcy and risk of angina
pectoris.8
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Population
In 1987 through 1989, the ARIC study12
recruited a population-based cohort of persons aged 45 to 64 years from
4 US communities. A total of 15 792 participants completed a home
interview and clinic examination. ARIC reexamined participants in
1990–1992 (93% return rate) and in 1993–1995 (86% return rate).
We defined hypertension as systolic blood pressure
140 mm Hg or diastolic blood pressure 90
mm Hg or current use of antihypertensive medication. We expressed
physical activity as a sport index ranging from 0 (low) to 5
(high).13 Technicians measured waist (umbilical
level) and hips (maximum) to compute waist/hip ratio. We computed body
mass index (kg/m2). Technicians measured average
carotid intima-media thickness using standardized B-mode
ultrasonography.14 15 We defined prevalent CHD at
baseline, for exclusion, as a reported history of a physician-diagnosed
heart attack, prior MI by ECG, prior cardiovascular
surgery, or prior coronary angioplasty. ARIC also measured
exertional angina by questionnaire16 and prior
stroke or transient ischemic attack through a standardized
interview. 140 mg/dL, nonfasting glucose 200 mg/dL, or a
physician diagnosis or pharmacological treatment for diabetes.
ARIC ascertained all CHD events in the
cohort.12 23 For the present study, we
included CHD events occurring between ARIC visit 1 and December 31,
1991. The median follow-up time was 3.3 years (maximum of 5 years). We
defined CHD incidence as (1) a definite or probable MI, (2) a silent MI
between examinations by ECG, (3) a definite CHD death, or (4) a
coronary revascularization.
We used a case-cohort design for the present study, in which
information on plasma tHcy, B vitamins, and related genotypes
was determined only for CHD cases and a stratified random sample of the
ARIC cohort. For this reference cohort, we oversampled participants
with thin average carotid intima-media thickness measurements at
baseline (<30th percentile) and also stratified the sampling by age
and sex.
In 1995, after ARIC had identified the incident cases and cohort
sample, technicians pulled these participants' baseline samples,
frozen in 1987–1989. The technicians thawed the frozen buffy coat,
extracted genomic DNA,24 treated it with a
proteinase K (1.9 µg/50 to 500 ng DNA), placed the DNA in multiple
aliquots, and froze them at –70°C. Approximately 90% of the sera
for tHcy had been thawed once or twice previously, and 10% had never
thawed. Previous evidence suggests tHcy is not altered with thawing and
refreezing (M.R. Malinow, MD, unpublished data, 1997). The plasma
aliquots for vitamin measurements had never been thawed.
The Oregon Regional Primate Research Center staff measured tHcy,
in duplicate, as the sum of free and bound homocystine, homocysteine,
and cysteine-homocysteine mixed disulfide using high-pressure liquid
chromatography and electrochemical detection based on
the method of Smolin and Schneider,25 as
previously described26 with minor
modifications.27 The laboratory interspersed 3
quality-control samples with the study samples each day; these
standards were 2 large, well-mixed pools obtained from American Red
Cross plasma. The laboratory adjusted tHcy levels to the mean of the
standard in each daily run to account for day-to-day method
variability. The staff of the Oregon Regional Primate Research Center
measured plasma folate and vitamin B12 by the
Quantiphase II Radioassay method supplied by Bio-Rad
Diagnostics Group and PLP using a radioenzymatic assay
supplied by Bühlmann Laboratories AG through American Laboratory
Products Co. To assess laboratory reliability, ARIC included
split-specimen, blinded duplicates prepared at the time of baseline
blood drawing. This yielded the following Pearson coefficients: tHcy,
r=0.95 (n=77); folate, r=0.97 (n=29); PLP,
r=0.90 (n=29); and vitamin B12,
r=0.91 (n=29).
We excluded participants with prevalent CHD, stroke, or
transient ischemic attack but not the 5% of participants whose
angina status was positive or unknown by the Rose questionnaire,
because the questionnaire's validity, especially in women, has been
questioned.31 We also excluded 6 participants
with creatinine >2 mg/dL, 21 participants who had
implausible values for energy intake, and 28 participants with missing
tHcy values. 
2 test. We performed supplemental
analyses using continuous instead of categorical independent
variables. We initially used 2 sex-specific models, 1 of which was
adjusted for age, race (black, white), and ARIC field center. In the
final multivariate model, we adjusted for sex, age,
race, field center, and the other factors related to CHD in this
sample: smoking status (never, former, current), total
cholesterol, HDL cholesterol, hypertension, and
diabetes. In addition, we adjusted dietary vitamin intake for energy
intake by including it as a continuous variable in the models.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Sample Characteristics
The sample included 232 incident CHD cases (146 definite or
probable MI, 19 silent MI, 30 definite fatal CHD, and 37
revascularization procedure) and a reference cohort
sample of 537 (of whom 10 were also CHD cases). Approximately 26% of
the CHD case subjects were black, and 75% were men.
In the cohort sample, plasma folate, vitamin
B12, and PLP all showed graded inverse
associations across tHcy quintiles (Table 1
). The weighted correlations of tHcy
with plasma folate, PLP, and vitamin B12 were
r=-0.29, r=-0.20, and
r=-0.28, respectively. Correlations among the
plasma vitamins were as follows: folate and vitamin
B12, r=0.44; folate and PLP,
r=0.48; and PLP and vitamin B12,
r=0.36. The correlations of plasma vitamins with estimated
dietary intake (without supplements) were as follows: folate,
r=0.15; B6 (with PLP),
r=0.24; and B12, r=0.04.
However, dietary intake of the 3 vitamins from foods was not
consistently associated with plasma tHcy in a graded fashion
(Table 1). The prevalence of vitamin supplement use decreased across
tHcy quintiles and was especially low (10%) in the highest quintile of
tHcy. Vitamin users had higher age-, sex-, race-, and field
center–adjusted mean plasma levels of vitamins than did
nonusers for folate (15 versus 8 nmol/L), PLP (98 versus 34
nmol/L), and vitamin B12 (359 versus 295 pmol/L).
Waist/hip ratio, alcohol intake, and hypertension were weakly but
positively associated with plasma tHcy concentration, but other CHD
risk factors were not.
View this table:
[in a new window]
Table 1. Age-, Race-, and Sex-Adjusted Mean Levels (or
Percentages) of Variables According to Quintiles of tHcy (ARIC,
Cohort Sample Only) 
). The prevalences of
heterozygosity and homozygosity of the thermolabile
MTHFRC677T mutation were 37% and 9%.
MTHFRC677T homozygosity increased across
each quintile of tHCy (Table 1), and the association carried a
P value for trend of 0.01.
Compared with the noncases, participants who subsequently
developed CHD tended to have a higher baseline mean tHcy concentration;
lower mean plasma concentrations of folate, PLP, and vitamin
B12; and lower supplemental vitamin use (Table 2). However, only the difference in mean
plasma PLP (19.0 nmol/L in CHD cases versus 31.5 nmol/L in noncases)
was statistically significant. Mean tHcy (in µmol/L) was 10.5
for participants with definite or probable MI, 9.8 for silent MI, 11.1
for definite fatal CHD, and 11.2 for
revascularization (P=0.63 for
difference).
View this table:
[in a new window]
Table 2. Age-, Race-, and Sex-Adjusted Geometric Mean Levels
(or Percentages) of Study Variables in Incident CHD Cases Versus
Noncases (ARIC)
Initial modeling of CHD incidence suggested interactions
(P
0.10) of sex with tHcy, plasma PLP, plasma folate, and
vitamin supplement intake, so we used sex-specific models initially. As
Table 3 illustrates, there was a positive
association of tHcy with CHD incidence in women (P for
trend=0.04), with an age-, race-, and center-adjusted relative risk of
2.53 for the highest quintile. There was no association in men. The
relative risk of CHD for those in the upper 10th percentile of tHcy
versus the lowest quintile was 3.48 (95% CI=0.96 to 12.6) in women but
was 1.07 (95% CI=0.3 to 3.4) in men. There also were statistically
significant age-, race-, and center-adjusted inverse associations of
CHD with plasma PLP in both sexes and with plasma folate in women.
Relative risks ranged from 0.36 to 0.48 for the fifth versus first
quintile (Table 3). There was no significant association of CHD with
dietary measures of B-vitamin intake (not shown). However, the age-,
race-, and center-adjusted relative risk of CHD for vitamin supplement
users versus nonusers was 0.47 (95% CI=0.22 to 0.97) in women
but 1.02 (95% CI=0.6 to 1.9) in men.
View this table:
[in a new window]
Table 3. Sex-Specific Age-, Race-, and Center-Adjusted
Relative Risks (95% CIs) of CHD in Relation to Quintiles of Plasma
tHcy or Vitamin Concentrations (ARIC) ), interactions by sex were not
significant (all P>0.09) after other risk factors were
considered. This fact, plus the small number of events in women, led us
to pool men and women for final modeling. As Table 4 shows, the
multivariately adjusted association of CHD with plasma
PLP was negative and statistically significant, with a relative risk
for the highest versus lowest quintile of 0.28 (95% CI=0.1 to 0.7).
Associations with CHD were positive for tHcy and negative for plasma
folate and B12, although none of these was
statistically significant. The multivariately adjusted
relative risk of CHD for vitamin supplement use was 0.79 (95% CI=0.5
to 1.4). Reanalysis of Table 4 excluding the blacks did not
change the conclusions.
View this table:
[in a new window]
Table 4. Multivariately Adjusted1
Relative
Risks (95% CIs) of CHD in Relation to Quintiles of Plasma tHcy or
Vitamin Concentrations (ARIC)
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In this prospective study, we found fasting tHcy to be associated
positively and relatively strongly at high levels with age-, race-, and
center-adjusted incidence of CHD in women, although not in men. Yet,
adjustment for other CHD risk factors abolished the association,
suggesting that tHcy was not independently associated with CHD. In this
same population, we previously observed a nonsignificant, positive
cross-sectional association in both men and women between tHcy and
carotid intima-media thickness.33 Most other
cross-sectional case-control studies have shown an association between
tHcy and CHD,1 34 35 but they have not uniformly
controlled for all confounding variables and are prone to survival
bias. Furthermore, tHcy is often elevated after an acute
coronary event.36 Although
cross-sectional studies have typically measured tHcy in cases at least
3 months after any acute CHD events, tHcy may have remained as a
consequence of CHD. 50% of the mutant
alleles in patients with homocystinuria.28 51
Yet, heterozygosity for these 2 mutations in this population-based
sample were too rare to be important determinants of elevated tHcy or
of CHD risk. We also found no association of CHD with the
CBS 68-bp insertion mutation, consistent with a
previous report.29
Selected Abbreviations and Acronyms
ARIC
=
Atherosclerosis Risk In Communities
CBS
=
cystathionine ß-synthase
CHD
=
coronary heart disease
MI
=
myocardial infarction
MTHFR
=
methylenetetrahydrofolate reductase
PLP
=
pyridoxal 5'-phosphate
tHcy
=
total homocysteine
Acknowledgments
The ARIC study was funded by contracts N01-HC-55015,
N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021,
and N01-HC-55022 from the US National Heart, Lung, and Blood Institute.
We thank Dr Lloyd Chambless, Dr Lin Clegg, Joy Liao, and Laura Kemmis
for technical assistance and the dedicated ARIC staff for study
implementation.
Footnotes
Reprint requests to Aaron R. Folsom, MD, Division of Epidemiology, School of Public Health, University of Minnesota, Suite 300, 1300 S Second St, Minneapolis, MN 55454-1015.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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