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Randomized Trial of Folic Acid Supplementation and Serum Homocysteine Levels
David S. Wald, MRCP;
Lucy Bishop, MRCP;
Nicholas J. Wald, DSc(Med);
Malcolm Law, FRCP;
Enid Hennessy, MSc;
Donald Weir, FRCP;
Joe McPartlin, PhD;
John Scott, ScD
Arch Intern Med. 2001;161:695-700.
ABSTRACT
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Background Lowering serum homocysteine levels with folic acid is expected to reduce
mortality from ischemic heart disease. Homocysteine reduction is known to
be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses
(relevant to food fortification) is unclear.
Methods We randomized 151 patients with ischemic heart disease to 1 of 5 dosages
of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood
samples for serum homocysteine and serum folate analysis were taken initially,
after 3 months of supplementation, and 3 months after folic acid use was discontinued.
Results Median serum homocysteine level decreased with increasing folic acid
dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine
reduction (placebo adjusted) was 2.7 µmol/L (23%), similar to the known
effect of folic acid dosages of 1 mg/d and above. The higher a person's initial
serum homocysteine level, the greater was the response to folic acid, but
there were statistically significant reductions regardless of the initial
level. Serum folate level increased approximately linearly (5.5 nmol/L for
every 0.1 mg of folic acid). Within-person fluctuations over time in serum
homocysteine levels, measured in the placebo group, were large compared with
the effect of folic acid, indicating that monitoring of the reduction in an
individual is impractical.
Conclusions A dosage of folic acid of 0.8 mg/d appears necessary to achieve the
maximum reduction in serum homocysteine level across the range of homocysteine
levels in the population. Current US food fortification levels will achieve
only a small proportion of the achievable homocysteine reduction.
INTRODUCTION
TAKING FOLIC acid lowers serum homocysteine levels. A dosage of 1 mg/d
has been shown in a meta-analysis1 to produce
the maximum homocysteine reduction, with no further reduction with higher
dosages, up to 5 mg/d. This maximum reduction is about 25% (or 3 µmol/L
from an average of 12 µmol/L).1 Given
the size of the association between serum homocysteine level and ischemic
heart disease shown in a cohort study,2 this
decrease in serum homocysteine level would be expected to lower ischemic heart
disease mortality rates by about 15%. Increasing average folic acid consumption
in the population is therefore likely to be important in reducing the incidence
of ischemic heart disease.
The effect of lower doses of folic acid on serum homocysteine concentration
remains uncertain. In the meta-analysis there were no data regarding whether
a dose lower than 1.0 mg would produce a maximum reduction.1
In view of the current interest in fortifying food with folic acid, it is
necessary to determine the lowest dose of folic acid that will produce the
maximum reduction in serum homocysteine level. To help answer this question,
we carried out a randomized, double-blind, placebo-controlled trial of folic
acid supplementation, to test the serum homocysteine–lowering effect
of dosages of 0.2, 0.4, 0.6, 0.8, and 1.0 mg of folic acid per day in patients
with known ischemic heart disease. The study also aimed to assess whether
there was any residual effect on serum homocysteine reduction 3 months after
folic acid supplementation had been stopped.
PATIENTS AND METHODS
Patients at St Richard's Hospital, Chichester, England, who were known
to have ischemic heart disease (previous myocardial infarction or angina)
were invited to participate in the study. The trial was approved by the local
research ethics committee. Patients already taking vitamin supplements or
taking anticonvulsant therapy were excluded from participating in the study.
Patients with a myocardial infarction in the previous 3 months were also excluded,
as serum homocysteine level increases in the acute phase after a myocardial
infarction and then decreases.3
A total of 151 patients were randomized to 5 folic acid supplementation
groups and a placebo group. Identical tablets containing no folic acid (placebo)
and doses of 0.2, 0.4, 0.6, 0.8, and 1.0 mg of folic acid (Cantassium Vitamins,
London, England) were used. The trial was double-blind. Bottles of tablets
were numbered in random order and dispensed in numerical order by the pharmacy.
The tablets were taken for 3 months.
Fasting blood samples for serum folate and serum homocysteine measurement
were taken from each patient on 3 occasions: before commencing the tablets,
after taking them for 3 months, and after stopping them for 3 months. The
blood samples were placed on ice immediately after collection and centrifuged
at 4°C within 2 hours, and the serum was stored at -20°C. Serum
homocysteine assays were performed at Trinity College, Dublin, Ireland, by
isocratic high-performance liquid chromatography,4
with the use of a fluorescent conjugate (SBD-1).5
A 1:10 dilution of 0.5 mL of whole blood in 1-g/L sodium ascorbate was also
stored at -20°C, until analyzed for serum folate by microbiologic
assay.6 Laboratory staff were unaware of the
randomization group to which patients were assigned.
Of the 151 patients (mean age, 65 years), 125 were male; 84 had had
a myocardial infarction and the other 67 had angina. There were 25 patients
each in the placebo, 0.4-mg, 0.6-mg, and 0.8-mg groups; 27 patients in the
0.2-mg group; and 24 patients in the 1.0-mg group. Three patients were unavailable
for follow-up at 3 months (1 in each of the placebo, 0.2-mg, and 0.4-mg groups),
and an additional 5 patients were unavailable for follow-up at 6 months (2
in both the placebo and 0.4-mg groups and 1 in the 0.2-mg group). In the other
groups, no patients were unavailable for follow-up. The effect of folic acid
after 3 months was determined from the 148 patients who attended the first
and second visits, and the effect of stopping folic acid supplementation was
determined from the 143 patients who attended all 3 visits.
At the clinic visit after 3 months of supplementation, all patients
said they had taken their tablets regularly. Counts of unused tablets in the
containers showed a maximum of 5 (of 91 initially), and more than half of
the patients had taken all their tablets.
RESULTS
Table 1 shows the initial
median (and mean) values and the values at the 10th and 90th percentiles for
serum homocysteine and serum folate concentrations. Figure 1 shows the distribution of initial serum homocysteine values
in the 151 patients; this was positively skewed. About 10% had serum homocysteine
levels greater than 20 µmol/L, compared with about 2% to 3% of individuals
without ischemic heart disease of the same age.2
These values remained high in the placebo group at the 3- and 6-month visits,
indicating that they were genuinely high and not simply the result of individual
fluctuations or measurement error. Because of the skewed distribution and
the presence of outlying values, the median was used instead of the mean as
a measure of central tendency.
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Table 1. Median, Mean, and 10th and 90th Percentiles of Serum Homocysteine
and Serum Folate Levels at Initial Visit (n = 151)
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Figure 1. Distribution of serum homocysteine
concentrations at initial visit.
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Figure 2A shows the median
increase in serum folate level between the initial and the 3-month visit according
to supplementation group (148 patients). Results were placebo-adjusted (subtracting
the median change in the placebo group from the median change in each supplementation
group). Serum folate level increased with increasing folic acid dose; for
each 0.1 mg of folic acid, serum folate level increased by about 5.5 nmol/L. Figure 2B shows the placebo-adjusted median
reduction in serum homocysteine levels between the initial and 3-month visit
according to supplementation group. Serum homocysteine levels showed a continuous
decline with increasing folic acid dose up to a dosage of 0.8 mg/d, where
the median serum homocysteine reduction was 2.7 µmol/L (23% of the median
starting homocysteine level in that supplementation group). The SEs of the
changes in serum homocysteine level from a linear regression analysis of the
change in serum homocysteine level on folic acid dose were about 0.7 µmol/L,
and while the trial did not have the statistical power to show statistically
significant differences between adjacent folic acid dosage groups, the trend
in increasing homocysteine reduction in relation to increasing folic acid
dosages up to 0.8 mg/d was significant. The high serum homocysteine response
in the 0.8-mg and 1.0-mg dosage groups was not due to a chance preponderence
of subjects with very high (>20 µmol/L) initial serum homocysteine levels
in these 2 dosage groups (the 0.8-mg group had none of these). The homocysteine
reduction with the 1-mg folic acid dose was slightly less than that with 0.8
mg; this is probably due to chance, but it does suggest that the effect of
1 mg is unlikely to be greater than that of 0.8 mg. The serum homocysteine–lowering
effect of folic acid was similar in older and younger patients. The mean reduction
in each supplementation group was a little greater than the median, and at
higher doses it was about 3 µmol/L (21% of the mean starting homocysteine
level), similar to the effect of folic acid dosages between 1 and 5 mg/d,
shown in the meta-analysis of the Homocysteine Lowering Trialists' Collaboration.1
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Figure 2. A, Median change in serum folate
concentration between initial and 3-month visits, adjusted for changes in
placebo group. To convert nanomoles per liter to micrograms per liter, divide
by 2.266. B, Median change (percentage change) in serum homocysteine concentrations
between initial and 3-month visits, adjusted for changes in placebo group.
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Table 2 shows the placebo-adjusted
reduction in serum homocysteine concentrations according to tertile groups
(thirds) of initial values. The size of the serum homocysteine reduction increased
with initial serum homocysteine level, as shown previously.1
The effect of folic acid in lowering serum homocysteine level was statistically
significant in all 3 tertile groups (P<.001, P<.001, and P = .04 from a
linear regression analysis in the highest, middle, and lowest tertile groups,
respectively). A folic acid dosage of 0.8 mg/d achieved the maximum median
reduction in serum homocysteine level in all 3 tertile groups, but in the
highest group a dosage of 0.4 mg/d appeared sufficient to achieve the maximum
effect. The results suggest that the higher the initial homocysteine level,
the lower the folic acid dose needed to attain the maximum reduction. This
trend was confirmed in the 10% of patients with very high initial homocysteine
levels ( 20 µmol/L). This group showed a dramatic response to folic
acid supplementation, even in the lowest dosage group, with a median serum
homocysteine reduction of 7.1 µmol/L (mean reduction, 9 µmol/L).
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Table 2. Reduction in Median Serum Homocysteine Level After 3 Months
of Folic Acid Supplementation*
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Table 3 shows the extent
to which the effect of folic acid on serum folate and serum homocysteine levels
was sustained 3 months after folic acid supplementation was stopped (143 patients
in total). Serum folate concentration decreased after cessation but (apart
from the 0.2-mg dosage group) did not return to initial levels; it was 9.3
nmol/L higher in the 0.8-mg/d supplementation group and 12.4 nmol/L higher
in the 1.0-mg/d supplementation group (the latter representing a 75% return
to the initial level). Serum homocysteine concentrations returned to near
initial levels for all supplementation groups, suggesting that a sustained
serum homocysteine reduction relies on continued folic acid supplementation.
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Table 3. Median Difference From Initial Median Serum Folate and Median
Serum Homocysteine Concentrations 3 Months After Stopping Folic Acid Supplementation
(Placebo-Adjusted), According to Dose of Folic Acid
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The 3 sets of measurements in 22 placebo-treated subjects allowed calculation
(from an analysis of variance) of the within- and between-person SDs for serum
homocysteine and serum folate levels (Table
4). For serum homocysteine, the between-person SD (6.8 µmol/L)
is large in relation to the within-person SD (2.3 µmol/L), indicating
that the variation across a single set of measurements is mainly due to true
differences between individuals rather than to random variation in the same
individual. Applying the data in Table 4 to prospective (cohort) studies of homocysteine and the incidence
of heart disease and stroke, the "regression dilution correction factor" (the
ratio of total to between-person variance) for serum homocysteine is 1.12
([2.332 + 6.762]/6.762), a low value, indicating
that the observed regression coefficient (slope) of cardiovascular disease
on homocysteine needs to be increased by only 12% to allow for the diluting
effect of random fluctuations in homocysteine level.7-8
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Table 4. Within- and Between-Person SDs for Serum Homocysteine and
Serum Folate Levels
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The data in Table 4 can
also be used to assess the value of using homocysteine measurements before
and after the start of folic acid treatment to monitor the homocysteine reduction.
This might be worthwhile if the effect of treatment were large in relation
to the within-person fluctuation in homocysteine level. In fact it is relatively
small, as shown by the "monitoring factor" for homocysteine of 0.45, so monitoring
in this way is not useful. This monitoring factor is the median reduction
from 0.8 mg of folic acid per day, divided by 2.56 times the within-person
SDs (which estimates the 10th to 90th percentile range of values in an individual
over time). For serum folate level, on the other hand, the monitoring factor
is large (3.5).
COMMENT
Our results show a clear effect of increasing folic acid dose on serum
homocysteine reduction. The maximum effect was attained at 0.8 mg/d, where
the serum homocysteine reduction was 2.7 µmol/L, a 23% reduction, similar
to the effect shown for folic acid dosages between 1 and 5 mg/d.1
The results confirm that the higher the initial serum homocysteine level,
the more sensitive is the response to folic acid. The study had the statistical
power to show that there was a significant serum homocysteine–lowering
effect of folic acid in people with relatively low initial serum homocysteine
levels, indicating some benefit in folic acid supplementation regardless of
serum homocysteine level. Although a dosage of 0.4 mg of folic acid per day
is sufficient to attain close to the maximum serum homocysteine reductions
in those with higher initial serum homocysteine concentrations, it will achieve
only about half of the smaller reductions in those with lower serum homocysteine
levels—overall, about 75% of the total effect. The higher dosage appears
necessary for the full benefit. The consistent pattern of our results, both
unstratified by initial serum homocysteine level (Figure 2B) and stratified according to initial serum homocysteine
level (Table 2), suggests that
we can be reasonably confident of the pattern of the dose-response relationship
observed between serum homocysteine level and supplemental folic acid despite
the fairly wide confidence intervals that apply to any one dosage group or
subgroup within a dosage group.
Table 5 summarizes the results
of published studies that have investigated the effect on serum homocysteine
level of folic acid supplements (in pills or fortified breakfast cereal) in
dosages less than 1.0 mg/d.9-15
Two studies in selected populations with very high serum homocysteine concentrations
(>40 µmol/L) were excluded.16-17
We also restricted our analysis to studies in which the mean age was more
than 40 years, because analysis of the published trials shows that the increase
in serum folate for a specified increase in folic acid in take is greater
in older than in younger people. It is likely, therefore, that for a given
intake of folic acid, homocysteine levels will decrease more in older than
in younger people. The data support our own results in suggesting that folic
acid dosages of 0.1 and 0.2 mg/d do not attain the full effect and that dosages
of 0.4 and 0.5 mg/d reduce serum homocysteine levels by about 20%—achieving
most but not all of the known maximum effect of about 25%. There is little
previously published information on dosages between 0.6 and 1.0 mg/d.
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Table 5. Serum Homocysteine Reduction in Trials Using Folic Acid at
Dosages Below 1 mg/d, in Which Mean Age of Subjects Was More Than 40 Years
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The data in Table 4 show
that the within-person fluctuation in serum homocysteine level over time is
large in comparison with the maximum average decrease in serum homocysteine
level produced by folic acid. It is therefore impractical to monitor the change
in serum homocysteine level produced by folic acid in an individual patient
(as opposed to a group); the relatively modest true reduction would be obscured.
On the other hand, the within-person SD of homocysteine is small in
relation to the between-person SD (2.3 vs 6.8 µmol/L), indicating that,
in cohort studies of serum homocysteine and cardiovascular disease, the "diluting"
effect of fluctuations in homocysteine will be small. The reduction in ischemic
heart disease mortality that can be expected through serum homocysteine reduction
should be close to the observed reduction in ischemic heart disease mortality
in cohort studies (systematic underestimation of the true effect will be only
about 10%). This compares with the larger effect of within-person fluctuation
in serum cholesterol level, where the effect of serum cholesterol reduction
on ischemic heart disease is about 50% greater than that estimated in cohort
studies.7-8
In an analysis of variance, such as that used to produce the results
in Table 4, it may be better to
adopt 2 modifications: to use logarithms (because the variation is likely
to be proportional to the mean) and to minimize the effect of outliers by
estimating the SD from the 10th to the 90th percentiles in the placebo group
to calculate the between-person SD. Analyzing the data in this way yields
estimates of 0.31 and 0.13 for the between- and within-person SDs of homocysteine
(units are loge), and 0.38 and 0.26, respectively, for serum folate.
These numbers can be made interpretable in the original units of measurement
by taking the antilogarithm and using this together with a mean value to calculate
the range defined by the mean ± 1 SD. For example, the range of mean
± 1 within-person SD for homocysteine with a mean of 10 µmol/L
would be 7.3 µmol/L (10 divided by antiloge 0.31) to 13.6
µmol/L (10 times antiloge 0.31). This compares with a range
of 7.7 to 12.3 µmol/L using the estimate in Table 4.
Our estimate for the homocysteine regression dilution correction factor
(1.12 from Table 4 or 1.18 from
the above estimates) is close to the estimate of 1.14 from Clarke and colleagues,18 but their estimates of both within- and between-person
SD were lower. This may reflect the lower homocysteine values in that study
(because the subjects did not have ischemic heart disease). An analysis of
variance using logarithms largely reconciles the differences between the 2
studies. In another study, the within-person SD of homocysteine was small
(0.6 µmol/L), but the duration of the study was short (4 weeks); the
between-person SD was 2.8 µmol/L.19
Public health initiatives that fortify food with folic acid are likely
to be the most effective means of increasing folic acid consumption in the
population. This is an inexpensive and simple strategy. Fortification has
already been introduced in the United States to prevent neural tube defects.
The level of fortification mandated by the US government (0.14 mg of folic
acid per 100 g of cereal grain, with the intention of supplementing a person's
diet by about 0.1 mg of folic acid per day)20
will achieve only a small proportion of the maximum serum homocysteine–lowering
effect. In the United Kingdom, the relevant government advisory committee
has recommended the universal fortification of flour at a level of 0.24 mg
per 100 g of flour.21 Even this will have only
a partial effect in lowering serum homocysteine level.
The advantages in selecting a study population with ischemic heart disease
were that they represent a significant proportion of people who stand to benefit
most from a reduction in serum homocysteine level through food fortification.
As expected, they had higher serum homocysteine concentrations than unaffected
persons of the same age (median, 13.4 µmol/L compared with about 12
µmol/L) and included a higher proportion of people with particularly
high serum homocysteine levels (likely to be caused by genetic variants, such
as homozygotes for the 677 methyltetrahydofolate reductase variant). This
important high-risk group stands to benefit considerably from serum homocysteine
reduction; their median serum homocysteine reduction of 7 µmol/L would
be expected to reduce risk by about 25%.2 Randomized
trials of the efficacy of folic acid supplements in the prevention of ischemic
heart disease are ongoing, but the existing evidence of an effect is persuasive.1 It would be reasonable for clinicians to consider
advising patients with ischemic heart disease to take 0.8 mg of folic acid
each day.
AUTHOR INFORMATION
Accepted for publication October 23, 2000.
This study was supported by the British Medical Association, London,
England (Brackenbury Research Award), and EU Biomed Project PL963549, Brussels,
Belgium.
We thank Jeremy Quiney, FRCP, Ray Lyon, MRPharmS, and staff in the biochemistry,
hematology, and pharmacy departments at St Richard's Hospital, Chichester,
England, and Lynn George and Tiesheng Wu at the Wolfson Institute of Preventive
Medicine, London, England. We also thank Robert Woodward, Melvyn Thomas, and
Baldeo Ramsarran of Cantassium Vitamins for making and supplying the folic
acid tablets.
Corresponding author and reprints: David S. Wald, MRCP, Department
of Cardiology, St Richard's Hospital, Spitalfield Lane, Chichester PO19 4SE,
West Sussex, England (e-mail: davidwald{at}hotmail.com).
From the Department of Cardiology, St Richard's Hospital, Chichester,
West Sussex, England (Drs D. Wald and Bishop); Wolfson Institute of Preventive
Medicine, London, England (Drs N. Wald and Law and Ms Hennessy); Department
of Clinical Medicine, St James's Hospital, Dublin, Ireland (Drs Weir and McPartlin);
and Department of Biochemistry, Trinity College, Dublin (Dr Scott).
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Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion
Refsum et al.
Clin. Chem. 2004;50:3-32.
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Phase II study of pemetrexed disodium (Alimta(R)) administered with oral folic acid in patients with advanced gastric cancer
Bajetta et al.
Ann Oncol 2003;14:1543-1548.
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A strategy to reduce cardiovascular disease by more than 80%
Wald and Law
BMJ 2003;326:1419.
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Folate and risk of cardiovascular disease
Wald et al.
BMJ 2003;326:1035-1035.
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Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study
van Oort et al.
Am. J. Clin. Nutr. 2003;77:1318-1323.
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News and Views on Folate and Elderly Persons
Lokk
J. Gerontol. A Biol. Sci. Med. Sci. 2003;58:M354-361.
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Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study
Venn et al.
Am. J. Clin. Nutr. 2003;77:658-662.
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Vitamin B-12 metabolism in HIV-infected patients in the age of highly active antiretroviral therapy: role of homocysteine in assessing vitamin B-12 status
Remacha et al.
Am. J. Clin. Nutr. 2003;77:420-424.
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Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease
De Bree et al.
Pharmacol. Rev. 2002;54:599-618.
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Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis
Wald et al.
BMJ 2002;325:1202-1206.
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Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age
Daly et al.
QJM 2002;95:733-740.
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Effects of Temperature on Stability of Blood Homocysteine in Collection Tubes Containing 3-Deazaadenosine
Hill et al.
Clin. Chem. 2002;48:2017-2022.
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The Serum Folate Response to the US Mandatory Fortification of Grain Products With Folic Acid
Wald et al.
Arch Intern Med 2002;162:2254-2254.
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Homocysteine and vascular disease
Robinson
Eur Heart J 2002;23:1482-1484.
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Folic Acid Intake from Fortification in United States Exceeds Predictions
Choumenkovitch et al.
J. Nutr. 2002;132:2792-2798.
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Folic Acid Fortification, Folate Status and Plasma Homocysteine
Rader
J. Nutr. 2002;132:2466S-2470.
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Vitamins for Chronic Disease Prevention in Adults: Scientific Review
Fairfield and Fletcher
JAMA 2002;287:3116-3126.
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Nationwide Folate Fortification Has Complex Ramifications and Requires Careful Monitoring Over Time
Rader and Yetley
Arch Intern Med 2002;162:608-609.
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Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease
Seshadri et al.
NEJM 2002;346:476-483.
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