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Plasma Total Homocysteine and Hospitalizations for Cardiovascular Disease
The Hordaland Homocysteine Study
Eha Nurk, MD;
Grethe S. Tell, PhD;
Stein Emil Vollset, MD, DrPH;
Ottar Nygård, MD;
Helga Refsum, MD;
Per M. Ueland, MD
Arch Intern Med. 2002;162:1374-1381.
ABSTRACT
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Background Elevated total plasma homocysteine (tHcy) level is a risk factor for
occlusive disease in the coronary, cerebral, and peripheral vessels and is
related to several lifestyle factors associated with cardiovascular disease
(CVD).
Objective To examine the association of a single tHcy measurement on subsequent
hospitalizations due to CVD.
Methods A population-based prospective cohort study was conducted from April
1, 1992, to May 31, 1998 (mean follow-up, 5.3 years) in western Norway. The
study included 17 361 individuals aged 40 to 42 or 65 to 67 years at
baseline. Main outcome measure was CVD as the main hospital discharge diagnosis
or coronary revascularization procedures (denoted "CVD hospitalizations")
during follow-up (n = 1275).
Results At baseline, participants with preexisting CVD had higher mean tHcy
values than individuals without CVD. Risk of CVD hospitalizations increased
significantly with increasing baseline tHcy only in the oldest age group.
Here, multiple risk factor–adjusted hospitalization rate ratios in 5
tHcy categories (<9, 9-11.9, 12-14.9, 15-19.9, and  20 µmol/L
[to convert tHcy to milligrams per liter, divide by 7.397]) were as follows:
1 (reference level), 1.00, 1.34, 1.67, and 1.94, respectively (P for trend <.001). The relation between tHcy level and CVD hospitalizations
was significantly stronger among individuals with preexisting CVD than those
without (hospitalization rate ratio per 5-µmol/L tHcy increment, 1.29
vs 1.10; P for interaction, .02).
Conclusions Plasma tHcy level is a strong predictor of CVD hospitalizations only
in elderly individuals, and especially among those with preexisting CVD. Our
findings are compatible with the theory that tHcy interacts with conventional
CVD risk factors to provoke the acute event of CVD.
INTRODUCTION
ELEVATED PLASMA total homocysteine (tHcy) concentration has been associated
with cardiovascular disease (CVD) and has, during the past few years, gained
acceptance as an independent and graded risk factor for arterial as well as
venous occlusive disease.1-3
While many prospective and retrospective studies, including a total of more
than 20 000 subjects, have shown such associations,1-4
other studies have not.4-9
Our group has previously reported10 that
an elevated tHcy level is a strong predictor of all-cause and CVD mortality
among patients with established coronary artery disease. Similar results have
been obtained from studies of free-living populations,11-13
demonstrating that elevated tHcy level is related to overall and CVD mortality.
The strongest dose-response effect of tHcy is usually observed during the
first few years of follow-up,7, 14-16
suggesting that tHcy may particularly be related to early acute events.
Elevation of tHcy is caused by several factors, among which deficiencies
of the B vitamins folate and B12 and impaired renal function are
the most common. In addition, elevated tHcy levels are associated with older
age, male sex, postmenopausal status, and lifestyle factors including smoking,
heavy coffee consumption, and lack of exercise.17
Weaker associations with other traditional CVD risk factors such as blood
pressure and serum cholesterol level have also been reported.2-4,17
The Hordaland Homocysteine Study is the largest population-based cohort
study of tHcy.17 Plasma tHcy was measured in
about 18 000 men and women who in 1992 and 1993 participated in a CVD
screening program, and the cohort has been followed up for mortality and cardiovascular
hospitalization end points. In this article, we report on the relationship
between baseline tHcy levels and subsequent hospitalizations with CVD as the
main discharge diagnosis or with coronary revascularization procedures (denoted
as "CVD hospitalizations").
SUBJECTS AND METHODS
STUDY PARTICIPANTS
The Hordaland Homocysteine Study is a collaboration between the National
Health Screening Service, local health services, and the University of Bergen,
Bergen, Norway. The source population included all individuals in Hordaland
County, in western Norway, aged 40 to 42 years; all individuals aged 65 to
67 years residing in Bergen and 3 neighboring suburban municipalities; and
a 2% random sample of 43- to 64-year-old residents in Bergen. The overall
baseline attendance rate was 72.7%. The analyses presented in this report
are based on the age groups 40 to 42 years and 65 to 67 years, a total of
17 361 individuals. All participating subjects gave their written informed
consent. The study protocol was approved by the Norwegian Board of Health,
the Data Inspectorate, and the Regional Committee for Medical Research Ethics
of Western Norway.
BASELINE DATA COLLECTION
Data collection procedures have previously been reported in detail17 and are only summarized here. Baseline measurements
included height, weight, blood pressure, and heart rate. Nonfasting levels
of serum total cholesterol, serum triglycerides, and plasma tHcy were determined.
Plasma tHcy, which includes both the free and protein-bound fractions of homocysteine
(Hcy), was determined by means of a fully automated high-performance liquid
chromatography assay.18-19
Self-administered questionnaires provided information about CVD risk
factors and lifestyle factors. Cigarette smokers were grouped in 5 categories:
never, former, light (1-9 cigarettes per day), moderate (10-19 cigarettes
per day), and heavy (20 cigarettes per day) smokers.
Information on preexisting CVD was obtained from a questionnaire completed
by the participant and checked by a nurse on the day of examination. The data
recorded included history of myocardial infarction, stroke, angina pectoris,
hypertension (defined as antihypertensive treatment), and diabetes mellitus.
In addition, ever having been diagnosed as having renal disease was reported.
Hyperlipidemia was defined as total cholesterol level greater than 270 mg/dL
(7.0 mmol/L). Data on baseline disease were missing for less than 0.5% of
all participating subjects. These were not included in the analyses stratified
by baseline CVD or hypertension.
OUTCOME VARIABLES
Computerized records containing discharge diagnoses for all hospitalizations
occurring between the baseline screening and May 31, 1998, at the 6 hospitals
serving Hordaland County were searched for CVD codes or procedures. Although
the exact figures are unknown, most hospitalizations among the study participants
took place within these 6 hospitals. The main hospital discharge diagnosis
(fatal and nonfatal events) according to the International
Classification of Diseases, Ninth Revision (ICD-9), was used to construct the following disease categories: coronary
heart disease (ICD-9 codes 410-414; n = 452); acute
myocardial infarction (ICD-9 code 410; n = 220);
cerebrovascular disease (ICD-9 codes 430-438; n =
202); aortic and peripheral arterial disease (ICD-9
codes 440-442 and 443.9-444; n = 67); pulmonary emboli and venous thrombosis
(ICD-9 codes 415, 437.6, and 451.1-453; n = 58);
and miscellaneous CVD (ICD-9 codes 390-398, 401-405,
416-429, 443.0-443.8, 446-448, 454-459, 780.2, 781.4, 782.3, 785.5-785.9,
786.0, 786.5, 794.3, 798-799, 996.0-996.1, 996.7, 997.0-997.2, V12.5, V15.1,
V42.1-V42.2, V43.2-V43.4, V45.0, V47.2, V53.3, and V71.7; n = 783). Coronary
revascularization procedures were grouped according to the Norwegian classification
of surgery, including percutaneous coronary intervention (n = 70) and coronary
artery bypass grafting (n = 104).
Information on causes of death, coded centrally by Statistics Norway
(Oslo), was obtained from death certificates for 310 deaths that occurred
in the cohort until February 28, 1997 (the latest date for which data on cause
of death were available to us). The underlying cause of death according to ICD-9 was used to identify deaths due to CVD. Altogether,
133 deaths were classified as cardiovascular, including 95 deaths due to coronary
heart disease (55 of these due to acute myocardial infarction), 21 due to
cerebrovascular disease, 5 due to aortic and peripheral arterial disease,
1 due to venous thrombosis, and 11 due to miscellaneous CVD.
STATISTICAL ANALYSES
The tHcy distribution was markedly skewed, and geometric means with
95% confidence intervals (CIs) are therefore presented. Relationships between
tHcy and CVD hospitalizations were studied by Kaplan-Meier estimation and
Cox proportional hazards model. Covariates were grouped and represented in
the model as indicator variables to assess nonlinearity in dose-response relationships.
Consistent with a previous report from the Hordaland Homocysteine
Study,20 cutoff levels for tHcy of 9, 12, and 15 µmol/L (to
convert tHcy to milligrams per liter, divide by 7.397) were chosen. For the
analyses of hospitalization rate ratio (HRR) by Cox regression, the highest
baseline tHcy group was divided in 2 (15.0-19.9 and 20 µmol/L),
to examine the effect of the highest tHcy levels. Analyses were carried out
for the total study population and separately for the 1587 individuals with
baseline CVD and/or hypertension (referred to as baseline CVD and based on
self-reported data about previous myocardial infarction [n = 354], stroke
[n = 125], angina pectoris [n = 491], and antihypertensive treatment [n =
1125]), and for the 15 691 individuals without baseline CVD or hypertension.
Individuals who died (n = 427) or emigrated from Norway (n = 80) during the
follow-up period were censored in the main analyses.
To estimate the HRR per 5-µmol/L tHcy increment, tHcy groups were
weighted by the median tHcy level in each group. Analyses were repeated with
hospitalizations for various cardiovascular diseases or coronary revascularization
procedures as end points and with testing for possible effect modification
of the tHcy-hospitalization relationship by different risk factors. A 2-sided P value less than .05 was considered significant.
RESULTS
Baseline characteristics according to tHcy levels are presented in Table 1. The proportion of participants
with preexisting CVD, hypertension, or hyperlipidemia generally increased
with increasing tHcy levels. Inverse and significant associations between
tHcy level and prevalence of diabetes mellitus were observed in both younger
and older men, but not in women. Smoking was strongly positively related to
tHcy level in all groups.
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Table 1. Baseline Characteristics by Plasma Total Homocysteine Levels
at the Beginning of the Study
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Individuals with baseline CVD or hypertension had significantly higher
tHcy levels than those without (10.6 µmol/L [95% CI, 10.2-11.0 µmol/L]
vs 9.9 µmol/L [95% CI, 9.9-10.0 µmol/L], P
= .001 in the youngest age group; and 12.0 µmol/L [95% CI, 11.9-12.2
µmol/L] vs 11.5 µmol/L [95% CI, 11.4-11.6 µmol/L], P<.001 in the oldest age group). The highest mean tHcy
level (12.8 µmol/L [95% CI, 12.5-13.2 µmol/L]) in the oldest participants
was seen among those with preexisting CVD or hypertension and who were hospitalized
with CVD during follow-up, whereas in the youngest participants those who
had preexisting CVD or hypertension, but were not subsequently hospitalized,
had the highest mean tHcy level (10.7 µmol/L [95% CI, 10.2-11.2 µmol/L]).
Those who did not report baseline CVD or hypertension and were not hospitalized
during follow-up had the lowest mean tHcy level (11.4 µmol/L [95% CI,
11.3-11.5 µmol/L] in the elderly and 9.9 µmol/L [95% CI, 9.9-10.0
µmol/L] in middle-aged individuals).
During the mean follow-up period of 5.3 years, 1275 individuals (7.3%)
were hospitalized either with CVD as the main discharge diagnosis or for coronary
revascularization procedures. The proportion hospitalized was about 5 times
higher in the oldest (22.0%) than the youngest (4.3%) men and about 4 times
higher in the oldest (12.7%) than the youngest (3.2%) women.
Kaplan-Meier plots of hospitalizations for CVD ("hospitalization-free
survival") according to baseline tHcy are shown in Figure 1. Although men had higher tHcy levels than women, the patterns
of associations between tHcy and hospitalizations were similar for both sexes,
and their data were combined in the analysis.
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Time to first hospitalization with cardiovascular disease (CVD) as
the main discharge diagnosis by baseline plasma total homocysteine levels:
Hordaland Homocysteine Study, 1992-1998. For all participants: 40 to 42 years
old: P = .20 (Kaplan-Meier log-rank test for differences between
homocysteine groups), P = .27 (Cox trend test adjusted
for age and sex), P = .79 (Cox trend test adjusted
for sex, baseline age, smoking status, diabetes mellitus, serum cholesterol
level, body mass index, and systolic blood pressure); 65 to 67 years old: P<.001, P<.001, P<.001, respectively. For CVD or hypertension at baseline: 40 to
42 years old: P = .34, P
= .45, P = .63, respectively; 65 to 67 years old: P<.001, P<.001, P<.001, respectively. For no CVD or hypertension at baseline: 40
to 42 years old: P = .20, P
= .31, P = .87, respectively; 65 to 67 years old: P<.001, P<.001, P = .007, respectively. To convert total homocysteine to milligrams
per liter, divide by 7.397.
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Baseline tHcy levels were not associated with subsequent hospitalizations
among the youngest participants. In contrast, the risk of CVD hospitalization
increased significantly with increasing baseline tHcy level in the oldest
age group, with the strongest association among those with baseline CVD or
hypertension. In the latter group, about 30% had been hospitalized because
of CVD at the end of the 5-year follow-up period (Table 2). To examine whether the risk differed for those with particularly
high tHcy levels, we divided the highest tHcy group in 2 (15-19.9 and 20
µmol/L). This showed further risk enhancement at tHcy levels above 20
µmol/L among the oldest participants, except for the group without baseline
CVD or hypertension.
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Table 2. Risk of Hospitalizations Due to Cardiovascular Disease* According
to Baseline Plasma Total Homocysteine Concentration
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We repeated the same analyses with a shorter follow-up period (mean,
4.2 years), including also individuals who suffered a fatal CVD event without
hospitalization. In the oldest age group with baseline CVD or hypertension,
the relative risk of a CVD event was 13% to 30% higher than the relative risk
obtained when CVD deaths outside hospitals were not included. The event rate
ratios in 5 tHcy categories (<9, 9-11.9, 12-14.9, 15-19.9, and 20 µmol/L)
were as follows: 1.0 (reference level), 1.21, 1.90, 1.80, and 3.02 (P for trend, <.001). Among the oldest individuals without
baseline CVD or hypertension, the relative risk of a CVD event was lower (except
the group of tHcy levels from 15-19.9 µmol/L) when the fatal CVD cases
were included: rate ratios in the same 5 tHcy categories were 1.0 (reference
level), 1.04, 0.97, 1.78, and 1.13, respectively (P
for trend, .02). No significant associations between baseline tHcy levels
and subsequent CVD events were found in the youngest age group either among
those with or those without baseline CVD or hypertension.
We also found that subjects with fatal CVD had higher mean tHcy values
at baseline than those with nonfatal CVD (youngest age group: 11.0 µmol/L
[95% CI, 9.5-12.7 µmol/L] vs 10.3 µmol/L [95% CI, 9.9-10.6 µmol/L]
[P = .36]; oldest age group: 13.4 µmol/L [95%
CI, 12.7-14.1 µmol/L] vs 12.4 µmol/L [95% CI, 12.2-12.7 µmol/L]
[P = .009]).
Inclusion of self-reported renal disease (339 subjects [3.4%] in the
youngest and 215 [6.0%] in the oldest age group) in the Cox regression model
did not alter the relative risk of hospitalization in the youngest group.
In the oldest age group, the HRR increased by approximately 10% in the 3 highest
tHcy categories.
The HRRs for several CVD discharge diagnoses per 5-µmol/L increment
in tHcy are shown in Table 3.
For the youngest age group, the numbers of events in the various subgroups
were low, and there were no significant trends of increasing hospitalization
risk with increasing baseline tHcy level in any subgroup. In the oldest age
group with baseline CVD or hypertension, a 5-µmol/L increment in tHcy
was associated with 53% higher risk of all CVD compared with 21% among those
without CVD or hypertension. In addition, whereas elderly persons with preexisting
CVD or hypertension were at particularly high risk for new CVD events (66%-144%
increase per 5-µmol/L tHcy increment), elderly persons without previously
known clinical vascular disease were at highest risk for coronary revascularization
procedures (60%-106% increase).
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Table 3. Risk of Hospitalizations Due to Various Cardiovascular Diseases
During a Mean Follow-up of 5.3 Years*
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Because elevated tHcy level was associated with a particularly high
risk in elderly persons with baseline CVD or hypertension, we evaluated whether
the association between tHcy level and hospitalization differed according
to various CVD risk factors. To attain optimal statistical power in these
analyses, the 2 age groups were combined. The effect of tHcy was modified
by baseline CVD or hypertension (P = .02) and by
hypertension without CVD (P = .03) (Table 4). Among those with 2 or more baseline risk factors (high
risk), the interaction between tHcy and CVD outcomes was borderline significant
(P = .07).
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Table 4. Effect Modification of the Association Between Plasma Total
Homocysteine and Cardiovascular Hospitalizations by Baseline CVD and Several
Risk Factors*
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COMMENT
In a large population-based cohort study of men and women, 40 to 42
and 65 to 67 years old, we have shown that tHcy level is a predictor of being
hospitalized for CVD during 5-year follow-up in the older but not the younger
age group. The relationship observed among the elderly was graded, independent
of other measured CVD risk factors, and applied to all of the major categories
of CVD. The association was strongest among those with preexisting CVD and/or
antihypertensive treatment, which is consistent with the study by Knekt et
al.21 They found an elevated risk of major
coronary heart disease events among women with higher serum Hcy levels and
preexisting CVD, but not among women free of CVD at baseline.
In contrast to our findings, some earlier studies22-23
among middle-aged individuals have found that elevated tHcy level confers
independent risk of occlusive vascular disease. Our study may lack statistical
power to detect a possible weak association between tHcy level and CVD morbidity
in the age group 40 to 42 years; only 3.7% were hospitalized, and more than
75% of the end points were classified as neither arterial nor venous occlusive
disease in this age group.
Smaller studies including about 20 subjects have reported an intraindividual
coefficient of variation for tHcy ranging from 7% to 11%.24-27
The 2 largest studies28-29 included
96 healthy subjects with a mean age of 69 years, 54 healthy subjects with
a mean age of 33 years, and 12 outpatients in a lipid clinic with a mean age
of 47 years; the intraindividual coefficients of variation were 9.0%, 9.4%,
and 9.3%, respectively. Thus, the intraindividual variation does not seem
to vary by age and cannot explain the lack of effect in the youngest subjects.
The lack of association in the youngest age group may be real. There
is evidence that tHcy may be a short-term risk factor,7
and the length of follow-up in the present study (5.3 years) should be sufficient
to detect a major effect of tHcy at least on combined end points of arterial
occlusive disease or coronary heart disease. Atherosclerosis is usually responsible
for about 80% of myocardial infarctions among patients younger than 45 years,30 and our results may therefore indicate that Hcy is
not a major etiologic component of atherosclerosis. This conclusion is also
supported by our previous finding among patients with angiographically verified
coronary artery disease, namely, that tHcy is more strongly related to subsequent
mortality than to the extent of coronary atherosclerosis at baseline.10 The role of tHcy in the progression of coronary atherosclerosis
has been evaluated angiographically in 2 recent prospective studies,31-32 and an effect of tHcy was demonstrated
in only 1 study.31
Current available data indicate that tHcy is related to acute or thrombotic
events,33 and the contribution of thrombosis
to atherothrombotic vascular disease may be particularly important at a young
age.34 Prothrombotic factors are, however,
not associated with CVD risk in the absence of other risk factors,34 and multiple factors are usually required to provoke
a CVD event early in life.35 Our study may
lack statistical power to detect such effect modification in the young group,
and the negative finding does not exclude that elevated tHcy is clinically
important in this subgroup. In fact, data from the total study population
indicated that the tHcy effect is modified by other risk factors. In particular,
the association between tHcy and hospitalization was stronger among individuals
with preexisting CVD or hypertension. Furthermore, high risk was observed
in diabetic patients. Although the association was not statistically significantly
different from nondiabetic patients, it supports previous findings of hyperhomocysteinemia
being particularly harmful in diabetic patients.36-38
Our results also concur with the observation in a large cross-sectional study
showing that elevated tHcy level may be particularly detrimental in patients
with hypertension.22 In contrast to that study,
we found the weakest tHcy effect among smokers, and we have recently made
a similar observation according to total and cardiovascular mortality within
the same cohort.20 This may suggest that the
association of tHcy with CVD is not due to confounding by smoking, and that
Hcy is not a major mediator of the smoking effect. The potential interaction
of tHcy with CVD risk factors has been discussed in a recent review.13
We found that the relative risk for CVD events increased up to 30% when
fatal CVD cases outside the hospitals were included in the model and that
subjects with fatal CVD had higher baseline mean tHcy values than subjects
with nonfatal CVD. These findings indicate that elevated tHcy level may reflect
severity of disease at baseline.
A key finding in the present study is an association between tHcy level
and hospitalization because of CVD, in particular among subjects with underlying
vascular disease or risk factors. This is in accordance with previous studies
on populations with high CVD risk.4, 13-14,20-21,33
Although a number of mechanisms have been suggested to explain the association,39 there is experimental evidence of acute vascular
effects of elevated tHcy level.40 The available
data therefore indicate that hyperhomocysteinemia is more strongly associated
with acute vascular events than with the slowly evolving atherosclerotic process.41
Traditional CVD risk factors and renal function are established determinants
of tHcy level,2-4,17
and elevated tHcy levels in patients with CVD have been attributed to subclinical
nephrosclerosis.13 The relative risk of hospitalization
increased about 10% among elderly subjects with tHcy levels greater than 12
µmol/L when the effect of baseline renal disease was controlled for.
Because the reliability of self-reported renal disease may be questioned,
these findings should be interpreted with caution. Markers of renal function
were not determined in the present study, and residual confounding may therefore
exist.
In the present study, individuals who had baseline tHcy levels greater
than 40 µmol/L (n = 67) were offered treatment with cyanocobalamin and/or
folic acid. About 2 to 3 years later, all 51 available subjects had tHcy levels
less than 20 µmol/L.42 Conceivably, tHcy
reduction by vitamin supplementation might have protected against CVD events
in some individuals with high tHcy levels. In that case, the CVD risk conferred
by elevated tHcy level might have been underestimated.
Strengths of our study included a cohort design, population-based samples,
a large number of participants (N = 17 361), and a relatively large number
of hospitalizations (N = 1275). Concentration of tHcy was measured only once,
but inferences based on a single exposure measurement usually underestimate
risks in prospective studies.43 We included
only hospitalizations with CVD as the main hospital discharge diagnosis or
coronary revascularization procedures. Although the validity of hospital discharge
diagnoses may be questioned, the use of only the main discharge diagnosis
should reduce this potential weakness. It is possible that the use of computerized
records containing discharge diagnosis may not be totally reliable with regard
to the true cause of underlying disease. However, we do not believe this to
have a major impact on our findings. Hospital records were retrieved from
all 6 hospitals in the area. Although it is possible that a few participants
could have been hospitalized for CVD elsewhere, failure to include these participants
should tend to weaken rather than strengthen our findings.
In conclusion, in this community-based 5-year follow-up study of CVD
hospitalizations among middle-aged and elderly adults, a strong association
with tHcy levels was observed only in elderly individuals, and especially
among those with baseline CVD. This suggests that tHcy primarily interacts
with established risk factors to provoke the CVD event leading to hospitalization.
AUTHOR INFORMATION
Accepted for publication October 23, 2001.
This study was funded by EU Commission Demonstration Project Contract
BMH4-CT98-3549, by the Research Council of Norway (Oslo), and by the Norwegian
National Health Association, Council on Cardiovascular Diseases (Oslo). Dr
Nurk is a fellow of the Research Council of Norway.
This study was presented in abstract form at the Third International
Conference on Homocysteine Metabolism, Sorrento, Italy, July 2-5, 2001; and
the Societies, Individuals and Populations joint conference of the Society
for Social Medicine and the International Epidemiological Association European
Group, Oxford, England, September 14, 2001.
Corresponding author and reprints: Eha Nurk, MD, Section for Preventive
Medicine, Department of Public Health and Primary Health Care, University
of Bergen, Armauer Hansen's Building, N-5021 Bergen, Norway (e-mail: eha.nurk{at}isf.uib.no).
From the Department of Public Health and Primary Health Care (Drs Nurk,
Tell, and Vollset), Institute of Medicine (Dr Nygård), and Department
of Pharmacology (Drs Refsum and Ueland) and Locus for Homocysteine and Related
Vitamins (Drs Nurk, Tell, Vollset, Nygård, and Ueland), University of
Bergen, Bergen, Norway.
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