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*
Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111;
Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 30333;
**
Division of Environmental Health Laboratory Sciences, Center for Environmental Health, Centers for Disease Control and Prevention, Chamblee, Georgia 30341; and
Division of Health Examination Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland 20782
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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40 y) male (n = 1097)
and female (n = 1107) participants in the third
National Health and Nutrition Examination Survey, excluding diabetics
and those supplemented with estrogen, vitamins or minerals, to evaluate
the association between serum tHcy concentration and self-report of
heart attack or stroke. After adjustment for age, race-ethnicity,
smoking, blood pressure, blood pressure medication, body mass index and
serum concentrations of creatinine and cholesterol, past events were
reported 2.4 (95% confidence interval 1.0–5.5) times as often by men
with tHcy concentration of >12 µmol/L as by men with lower values.
The odds ratio for women was 2.6 (95% confidence interval 1.1–6.6)
after adjustment for the same factors plus menopausal status. A
stronger relation in men aged 
60 y compared with older men may help
reconcile conflicting results of earlier studies.
KEY WORDS: • homocysteine • myocardial infarction • stroke • survey • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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). Although one
(Perry et al. 1995
) prospective study reported an odds
ratio
(OR)4for stroke of 2.8 for serum total homocysteine (tHcy) concentration in
the fourth quarter of the distribution compared with the first and a
strong dose-response relation, four other prospective studies did
not support these conclusions (Arnesen et al. 1995
,
Evans et al. 1997
, Folsom et al. 1998
,
Wald et al. 1998
). After 5 y of follow-up,
subjects in a sixth prospective study who were in the upper 5% of the
tHcy distribution had 3.4 times the heart attack risk of those in the
lower 90% (Stampfer et al. 1992
), but the OR was lower
and not significant after longer follow-up (Chasan-Taber et al. 1996
, Verhoef et al. 1994
). The different
findings of the prospective and retrospective studies could reflect the
greater ability of the former to eliminate bias and distinguish cause
from effect. Alternatively, results of both sets of studies could be
valid for different population subgroups. For example, Wald et al. (1998)
noted that mean age at event was >60 y in three
prospective studies with negative or equivocal findings but <60 y in
eight retrospective studies with positive results. Data from the third
National Health and Nutrition Examination Survey (NHANES III) afford a
unique opportunity to examine the association in U.S. men and women
across a broad range of ages. |
SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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The NHANES III, conducted by the National Center for Health Statistics
(NCHS), Centers for Disease Control and Prevention, obtained nationally
representative data on the health and nutritional status of the
civilian, noninstitutionalized U.S. population through interviews and
physical examinations (NCHS 1996
). To accomplish this
goal, some population subgroups (i.e., young children, older persons,
blacks and Mexican Americans) were oversampled. All respondents gave
their informed consent, and the NHANES III protocol was reviewed and
approved by the NCHS NHANES Institutional Review Board.
Homocysteine measurement.
tHcy concentrations, which were measured as an NHANES III, Phase 2,
surplus serum project, were available for 8585 (63%) of the 13,635
Phase 2 sample members aged 12 y. The response rate among those aged
40 y, the subgroup of interest in this investigation
(n = 7052), was 59%. Blood was drawn at mobile
examination centers from examined persons across a range of fasting
states and was processed according to a standard protocol (NCHS 1996
). Serums were stored at -70°C for 8 mo to 3 y
before tHcy analysis. tHcy was measured by HPLC (Araki and Sako 1987
) at the U.S. Department of Agriculture Human Nutrition
Research Center on Aging after approval by the New England Medical
Center Human Investigations Review Committee and the Surplus Serums
Bank Steering Committee.
Data analysis.
This report focuses on the 1097 male and 1107 female survey
participants aged 40 y with complete data on tHcy concentration and
various vascular disease correlates, excluding those with certain
conditions or habits known to alter tHcy metabolism (i.e., abnormal
liver function, as indicated by aspartate aminotransferase or alanine
aminotransferase of >58 U/L, self-report of diabetes
or current supplementation with estrogen, vitamins or minerals).
To account for certain complexities of the NHANES III survey design
(i.e., a staged sampling scheme and unequal probability of subject
selection and nonresponse), data were analyzed using SUDAAN software
(Shah et al. 1996
). Analyses were carried out separately
for four sexxage subgroups created by dividing male and female
subjects into two age groups at the median age of 60 y.
Electrocardiogram results were unavailable when this study was initiated, and we used interview responses to classify subjects as cases (i.e., self-report of one or more previous heart attack or stroke) and noncases. Noncases whose responses indicated possible angina (n = 86) were excluded.
We used least-squares means generated by SUDAAN PROC REGRESS and proportions generated by SUDAAN PROC CROSSTAB to describe the four subgroups of subjects according to serum tHcy concentration and the following potential confounders of the main relation of interest: age at examination, sex, race-ethnicity, body mass index, pack-years of cigarette smoking, systolic blood pressure, diastolic blood pressure, use of blood pressure medication, menopausal status (women) and serum concentrations of creatinine, total cholesterol and HDL cholesterol. We also used multiple linear and logistic regression modeling (SUDAAN PROC REGRESS, SUDAN PROC RLOGIST) to identify factors significantly related to past heart attack or stroke after adjustment for all other factors. Finally, we used SUDAAN PROC RLOGIST to generate OR and 95% confidence intervals for the relation between previous heart attack or stroke and serum tHcy concentration above the 75th percentile of the distribution of the noncases (i.e., 12 µmol/L) compared with a lower concentration and for a 5-µmol/L increase in serum tHcy concentration. P < 0.05 was considered statistically significant for all analyses.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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, 2
), self-reported history of heart attack or stroke was significantly
related to higher serum tHcy concentration in both men and women
(Table 3
). Hyperhomocysteinemic subjects, whether male or female, reported a
past heart attack or stroke 
2.5 times as often as
nonhyperhomocysteinemic subjects, and in both sexes, reports of past
events increased by 50% per 5-µmol/L increase in serum tHcy
concentration of >10 µmol/L. Significant relationships were observed
only for younger men and older women, but age interacted significantly
with serum tHcy concentration in relation to heart attack or stroke
only in the men. Results were similar for the older subjects regardless
of whether subjects whose first heart attack or stroke had occurred at
age 60 y were included (data not shown). Multivariate
modeling also revealed that past heart attack or stroke was positively
related to male sex, non-Hispanic black race-ethnicity, age,
cigarette smoking, total cholesterol concentration and postmenopausal
status and that age interacted significantly with cigarette smoking in
men and with HDL cholesterol concentration in women in a manner similar
to that observed for tHcy concentration (data not shown).
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In retrospective studies, two alternatives to the suspected
cause-and-effect association must be considered: 1) that the
relation is not causal and 2) that the direction of the
relation is opposite to that hypothesized. Hyperhomocysteinemia has
been linked to certain established risk factors for occlusive vascular
disease such as sex, cigarette smoking and age (Refsum et al. 1998
), but we accounted for these and other potential
confounders. Reliance on self-reported end points can cause
nondifferential misclassification and consequent underestimation of OR.
Upward bias is also possible (Walker et al. 1998) but
unlikely given the subjects’ ignorance of their tHcy concentrations.
Finally, failure to find associations could be explained by the absence
from the survey of fatal cases; these patients might have had the
highest tHcy concentrations (Nygård et al. 1997
). Given
the different results for the different sexxage subgroups, however,
such scenarios probably do not explain our findings.
Heart attacks or strokes might cause hyperhomocysteinemia through a
general inflammatory response, medication use, renal impairment or
other concomitant disease (Christen et al. 2000
). We
tried to control for some of these possibilities through exclusion
criteria and by controlling for serum creatinine concentration, a crude
index of renal dysfunction (Berkow 1999
). Furthermore,
OR were not affected by controlling for serum C-reactive protein, a
nonspecific marker of inflammation (Ford and Giles 2000
), despite a strong association between this factor and
past heart attack or stroke in men of all ages (data not shown).
The sex differences we found, which have not been noted before, could
reflect the different times in the lives of men and women when tHcy
becomes important relative to occlusive vascular disease. Occlusive
vascular events occur rarely in young women, but risk rises rapidly
after menopause (Boers et al. 1983
). Furthermore, we
have shown previously with the NHANES III data that tHcy concentration
is inversely related to estrogen status (Morris et al. 2000
) and that the tHcy concentrations of women remain fairly
stable, and significantly lower than those of comparably aged men,
until menopause (Jacques et al. 1999
).
The results of this study emphasize the need to consider age and sex when interpreting results from studies of the relation between serum tHcy concentration and occlusive vascular events.
Whether a causal association exists between tHcy and vascular disease
remains unresolved. Several studies have reported an inverse
association between folate status and tHcy concentration; others have
demonstrated a tHcy-lowering effect of folic acid administration
(Boushey et al. 1995
, Malinow et al. 1998
). Studies of the effect of tHcy lowering on the risk of
occlusive vascular disease are eagerly awaited.
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FOOTNOTES |
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2 The contents of this publication do not
necessarily reflect the views or policies of the U.S. Department of
Agriculture, nor does mention of trade names, commercial products, or
organizations imply endorsement by the U.S. Government.
4 Abbreviations used: NCHS, National Center for
Health Statistics; NHANES III, third National Health and Nutrition
Examination Survey; OR, odds ratio; tHcy, total homocysteine.
Manuscript received December 16, 1999. Revision accepted August 11, 2000.
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REFERENCES |
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