 |
|
Hyperhomocystinemia
A Risk Factor or a Consequence of Coronary Heart Disease?
Paul Knekt, PhD;
Antti Reunanen, MD, PhD;
Georg Alfthan, PhD;
Markku Heliövaara, MD, PhD;
Harri Rissanen;
Jukka Marniemi, PhD;
Arpo Aromaa, MD, PhD
Arch Intern Med. 2001;161:1589-1594.
ABSTRACT
| |
Background Mild hyperhomocystinemia has been suggested as an indicator of an increased
risk of cardiovascular disease.
Objective To examine whether serum homocysteine concentration is a predictor of
coronary heart disease (CHD) events.
Methods A case-control study, nested in a population-based cohort study was
used. During a follow-up of 13 years, 166 major coronary events (death from
CHD or nonfatal myocardial infarction) occurred in men with evidence of heart
disease at baseline and 272 events in men without a history of heart disease.
Two controls per case were selected by individual matching.
Results Among men with known heart disease at baseline, the relative risk (95%
confidence interval) of CHD events adjusted for age, smoking, hypertension,
diabetes mellitus, serum cholesterol level, body mass index, and alcohol consumption
was 2.23 (95% confidence interval, 1.03-4.85) in the highest serum homocysteine
quintile compared with the lowest quintile. Among the men free of heart disease
at baseline, the corresponding relative risk was 0.90 (95% confidence interval,
0.51-1.60).
Conclusions This prospective study does not support the hypothesis that a high concentration
of serum homocysteine is a risk factor for coronary events in a population
free of heart disease. However, it does suggest that mild hyperhomocystinemia
predicts secondary coronary events in men with heart disease, possibly as
a consequence of atherosclerotic changes.
INTRODUCTION
AN ELEVATED plasma concentration of homocysteine has been suggested
to be a new important risk factor of atherosclerotic vascular disease amenable
to preventive actions.1-3
Experimental evidence suggests that an increased concentration of homocysteine
may result in vascular changes through several mechanisms.4-6
Homocysteine has been shown to impair vascular endothelial cell function and
even induce cell damage. In addition, homocysteine is a stimulator of smooth
muscle cell proliferation. It may also induce oxidation of low-density lipoproteins.
Thrombogenesis is enhanced by a high concentration of homocysteine, increased
adherence of platelets, inhibition of protein C activation, expression of
thrombomodulin, and decreased activity of tissue-type plasminogen activator.
Several case-control studies have provided consistent evidence showing higher
serum homocysteine concentrations in patients with various atherosclerotic
diseases compared with healthy control subjects.1, 5, 7-8
Accordingly, the homocysteine risk factor hypothesis has won large acceptance
and several authors1, 9-12
have argued that screening and preventive measures should be undertaken at
least in persons with known atherosclerotic disease. Folic acid is known to
be an effective factor in reducing elevated levels of serum homocysteine,
and several intervention studies have been initiated to investigate the effect
of supplementation of the vitamin on hyperhomocystinemia risk and in secondary
prevention among individuals with known atherosclerotic diseases.13-14
The fact remains that the hypothesis has been strongly based on biological
mechanisms mostly demonstrated by in vitro studies and that the human evidence
mainly comes from case-control studies whereas population-based prospective
cohort studies have given conflicting results. Several cohort studies showed
a significantly elevated risk of coronary heart disease (CHD) at higher serum
homocysteine levels.15-21
Other studies demonstrated an increased risk only in subpopulations,22 for short follow-up periods,23
or only when the results were not adjusted for all potential confounding factors.24-25 A complete lack of association between
hyperhomocystinemia and CHD has also been reported.26-29
Thus, despite the flourishing literature on homocysteine as a potential new
vascular risk factor, uncertainty still prevails about whether hyperhomocystinemia
reflects the primary cause of vascular disease or is involved in the development
of secondary events in populations suffering from atherosclerosis.
To further elucidate the role of homocysteine as a risk factor for CHD
events, we examined its predictive value in a prospective population study
with a long follow-up and large enough sample size to enable separate consideration
of future CHD cases with and without heart disease at the baseline examination.
SUBJECTS, MATERIALS, AND METHODS
A total of 3471 men, aged between 45 and 64 years, participated in the
Mobile Clinic Health Examination Survey that was carried out in various regions
of Finland from January 1, 1973 through December 31, 1976.30
The individuals participated with the understanding that these data would
be used in scientific research. A self-administered questionnaire provided
information about the history of diseases, medicine use, recreational physical
activity, alcohol consumption, and smoking habits. The answers to this questionnaire
were checked and, if necessary, specially trained nurses assisted subjects
in its completion. Casual blood pressure was registered, and the subjects
were classified into 4 hypertension categories based on their systolic and
diastolic blood pressures and their use of antihypertensive drugs.31 Body height and weight were measured and the body
mass index (calculated as weight in kilograms divided by the square of height
in meters) was computed. Serum cholesterol concentrations were determined
from serum samples after 13 weeks of storage at -20°C with an autoanalyzer
modification of the Burchard-Liebermann reaction. Patients with heart disease
were identified based on disease history. Patients with diabetes mellitus
were identified on the basis of disease history, use of antidiabetic medication,
or the results of an oral glucose tolerance test. A history of heart disease
was obtained using specific questions: Have you had, according to a physician's
diagnosis, myocardial infarction, angina pectoris, heart failure, or valvular
or congenital heart disease? Of the 3471 men, 884 reported a history of heart
disease.
Nonfatal cases of myocardial infarction (International
Classification of Diseases, Eighth Revision code 410) were identified
by linking the study population to the nationwide hospital discharge register
using a unique personal identification number.32
The fatal cases of CHD (International Classification of
Diseases, Eighth Revision codes 410-414) were identified from death
certificates that were obtained for all the deceased from Statistics Finland,
Helsinki. For persons with several CHD events, the first one was registered.
The follow-up covered cases occurring between the baseline examination and
the end of 1985. During this follow-up period 166 major CHD events (coronary
deaths or myocardial infarction) occurred among the men with heart disease
and 272 such events among those free of heart disease at baseline.
A nested case-control design was adopted to study the ability of the
serum homocysteine level to predict major CHD events. Two controls per case
were selected by individual matching using age, municipality, and presence
of heart disease at baseline as matching variables. The ages were matched
by nearest available matching. Matching for municipality also controlled for
the time of the baseline examination and for the duration of serum sample
storage.33 Serum samples for some of the controls
were for different reasons unavailable and, thus, the final numbers of controls
were 311 and 524 for those cases with and without heart disease at baseline,
respectively.
The serum samples were stored at -20°C until 1996 when they
were used in the present study. The serum samples for each case and individually
matched controls were analyzed simultaneously in random order independently
of case-control status of which the laboratory personnel were unaware. The
levels of total serum homocysteine, cysteine, and cysteinylglycine were determined
by a modification of the high-pressure liquid chromatographic method described
by Ubbink et al.34 Our mobile phase was modified
to consist of 0.37-mol/L acetate and 0.5% methanol, pH 4.15. The peak heights
were calibrated using a secondary serum standard. The precision between each
series for an in-house serum pool was 3.3% at a level of 6.5 µmol/L.
The accuracy was verified by participating in an interlaboratory quality control
scheme in which the bias was null for serum at 9.5 µmol/L and +1% for
serum at 38.1 µmol/L.35
The conditional logistic model was used to estimate the relative risks
(as odds ratios) of CHD events between quintiles (based on the distribution
among all controls) of serum homocysteine.36
The effects of potential confounding factors were adjusted for by including
them in the model. Test for trends was performed by including homocysteine
as a continuous variable in the model. Age-adjusted mean levels of potential
confounding factors at baseline in quintiles of serum homocysteine were estimated
using the general linear model.37
RESULTS
In men free of heart disease at baseline, differences were observed
between subjects with incident CHD events and their controls in several (smoking,
hypertension, diabetes mellitus, body mass index, serum cholesterol level,
and serum triglyceride levels), but not all, (leisure time physical activity
and alcohol consumption) cardiovascular risk factors (Table 1). No differences were observed for the levels of serum homocysteine,
cysteine, or cysteinylglycine. The differences in cardiovascular risk factors
between cases and controls in men with known heart disease at baseline were
similar. In that subpopulation, however, the mean serum homocysteine concentration
was significantly (9%) higher in cases than in controls. The age-adjusted
serum homocysteine level among future CHD events with known heart disease
at baseline was 11% (P = .01) higher than in those
future CHD events free of heart disease at baseline.
|
|
|
|
Table 1. Mean Values of Different Variables in Patients With Coronary
Heart Disease Events and Control Subjects
|
|
|
Serum homocysteine concentration increased significantly with age (Table 2). It was also directly proportional
to the prevalence of arterial hypertension and to the level of serum triglycerides.
Furthermore, serum homocysteine concentration was strongly associated with
the serum cysteine level and weakly associated with the serum cysteinylglycine
level.
|
|
|
|
Table 2. Mean Values* of Different Variables in Quartiles of Serum
Homocysteine Among All Controls Combined
|
|
|
No association between serum homocysteine concentration and the incidence
of major CHD events was observed in men originally free of heart disease (Table 3). The relative risk between individuals
in the highest and lowest quintiles of serum homocysteine was 1.00 (95% confidence
interval [CI], 0.61-1.63). A similar comparison between the highest and lowest
deciles gave a corresponding value of 1.11 (95% CI, 0.55-2.25). In men known
to have heart disease at baseline, however, there was a positive association
between the serum homocysteine level and the incidence of major CHD events.
The relative risk of such an event between the highest and lowest homocysteine
quintiles was 2.15 (95% CI, 1.10-4.22). Adjustment for the known risk factors
of CHD, ie, smoking, hypertension, diabetes mellitus, serum cholesterol level,
body mass index, and alcohol consumption, did not notably alter the result
(Table 3).
|
|
|
|
Table 3. Relative Risk of Coronary Heart Disease Events Between Quintiles
of Serum Homocysteine*
|
|
|
An examination of possible effect-modification by sex, age, body mass
index, smoking, hypertension, diabetes mellitus, and high body iron stores
(ferritin) on the association between the homocysteine level and the risk
of major CHD events generally revealed no significant interactions (data not
shown). However, in men suffering from heart disease at baseline, there was
a strong positive association between the homocysteine concentration and the
major CHD events in the lowest tertile of serum ferritin. In this category
the relative risk of CHD events between the highest and lowest quartiles of
homocysteine was 7.11 (95% CI, 2.05-24.74).
A study of the association as a function of follow-up time suggested
strong associations for shorter follow-up times both in men with and without
heart disease at baseline. The relative risks of major CHD events between
the highest and lowest quintiles of homocysteine during the first 2 years
of follow-up were 4.44 (95% CI, 1.01-19.50) and 2.38 (95% CI, 0.53-10.64),
respectively, in the 2 subgroups of men.
COMMENT
We found that an elevated serum concentration of homocysteine predicted
CHD events in men with evidence of known heart disease at the baseline examination.
In men without a history of heart disease, however, homocysteine did not predict
future disease. Our results do not therefore corroborate the hypothesis that
homocysteine concentration is a causal factor in the pathogenesis of atherosclerosis
in healthy populations. Similar negative findings were reported in another
prospective population study in Finland26 and
in several recent cohort studies.22, 24, 27-29
However, since the first published prospective population study showing an
independent predictive effect of homocysteine concentration on myocardial
infarction incidence,15 several similar positive
results from prospective population studies have been reported.16-21
The conflicting results may be due to several factors. First, the elevated
homocysteine levels could, in fact, be a marker or consequence of atherosclerosis
and, thus, have no relevance in the prediction of the disease. Particularly
the earlier epidemiological evidence on the risk factor role of plasma homocysteine
came mainly from case-control studies based on cases with established atherosclerosis1, 38-40 and,
thus, is compatible with the consequence hypothesis. Our finding of an elevated
CHD event risk at higher serum homocysteine levels during the first year of
follow-up also in men free from heart disease at baseline could be due to
the presence of symptom-free men. The conflicting results obtained from the
Physicians' Health Study with short15 and longer27 follow-up can be similarly explained. Furthermore,
3 of the prospective studies reporting an elevated risk at higher serum homocysteine
levels had a rather short follow-up period.16, 19-20
However, in the British Regional Heart Study21
the length of follow-up was unrelated to the strength of association. An elevated
serum homocysteine concentration might also be a marker of progression of
the atherosclerotic process and, thus, may be a risk indicator or a risk factor
among men with atherosclerotic vascular disease. Our finding demonstrating
an increased subsequent CHD event risk in men with known heart disease at
baseline is in accord with this hypothesis. The British Regional Heart Study21 also reported a stronger association in men with
preexisting CHD at baseline than among others. Furthermore, high homocysteine
levels predicted a subsequent increase in complications in patients with atherosclerotic
vascular disease in other studies.41-42
The discrepant results obtained from prospective population studies could
partly be explained by the existence of a varying proportion of individuals
with known or unknown atherosclerotic disease at the baseline examination
in some of the studies.19-20 This
interpretation is also in accord with the consistent associations reported
in case-control studies.
Second, the strength of association of homocysteine concentration and
atherosclerosis may vary between populations. The genetic background of the
Finnish population differs somewhat from that of the populations from other
Western countries. Thus, some hereditary disorders common in other countries
are rare in Finland, whereas many hereditary disorders occurring in Finland
are rare in other countries.43-44
Homocystinuria is one of the hereditary disorders that is rare in Finland.43 As in our study, one earlier report could not find
any effect of serum homocysteine concentration on the risk of atherosclerotic
diseases in Finnish people free of heart disease at baseline.26
These findings could partly be explained by the rarity of genetically determined
disorders in Finnish people leading to elevated levels of serum homocysteine.
The strength of association may also vary from one subpopulation to another,
according to single effect-modifying factors, such as sex,22
age,21 and hypertension,19
or clusters of several cardiovascular risk factors. In this study, we found
no notable interactions with known cardiovascular risk factors.
Third, the serum homocysteine concentration may be associated with established
risk factors and, thus, the observed association could be due to uncontrolled
confounding factors. As in earlier studies,5, 45
we found that age, hypertension, body mass index, and serum triglyceride levels
were associated with the level of homocysteine. In the Caerphilly Prospective
Study,24 in which a significantly increased
risk associated with high homocysteine levels was observed, statistical significance
was not reached once other risk factors were controlled for. In another British
prospective study, the British United Provident Association Study,17 the significance of the association for serum homocysteine
was reported after controlling only for systolic blood pressure and serum
apolipoprotein B. In our study, as well as in another,21
adjustment for potential confounding factors did not appreciably alter the
strength of the association.
Fourth, the lack of association may be owing to poor reliability of
serum homocysteine determination. The analytical variation in our study was,
however, acceptably low. The long storage of our serum samples at -20°C
could potentially weaken the reliability of serum determinations. It has,
however, been shown that the length of storage time apparently does not lead
to alterations in homocysteine concentrations.26
Furthermore, all serum samples had undergone the same freeze-thaw history
and were analyzed within a short time without knowledge of the case-control
identification. The fact that we found an association among men with heart
disease also suggests that the reliability of serum homocysteine determination
was adequate.
Finally, although there are several possible mechanisms by which a high
homocysteine level may promote pathogenesis of atherosclerosis,46
doubts of the causal role have recently been raised. Evidence has been presented
that plasma homocysteine level increases after tissue damage and raised plasma
levels of homocysteine promote endothelial damage and adhesion of leukocytes
to the endothelial surface.47 A high plasma
homocysteine level, thus, would be an indicator of continuing tissue damage
and a promotor or enhancer of inflammatory thickening of vascular wall47 rather than an initiator of atherosclerosis. Causal
association of hyperhomocystinemia and vascular disease has also been questioned
in a recent review of epidemiological studies48
concluding in agreement with our results, that raised homocysteine level would
merely be a marker of atherosclerosis and a consequence of other factors rather
than a primary risk factor.
CONCLUSIONS
Our prospective data demonstrating the ability of high serum concentrations
of homocysteine to predict secondary CHD events in middle-aged men with heart
disease do not support the hypothesis that a high homocysteine concentration
is a primary causal factor in the pathogenesis of atherosclerosis, but merely
suggest it to be a consequence of atherosclerotic changes.
AUTHOR INFORMATION
Accepted for publication December 11, 2000.
Corresponding author: Paul Knekt, PhD, National Public Health, Mannerheimintie
166, 00300 Helsinki, Finland (e-mail: paul.knekt{at}ktl.fi).
From the National Public Health Institute, Helsinki, Finland (Drs Knekt,
Reunanen, Alfthan, Heliövaara, and Aromaa and Mr Rissanen); and the Social
Insurance Institution, Turku, Finland (Dr Marniemi).
REFERENCES
| |
1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for
vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.
ABSTRACT
2. Oakley GP Jr. Eat right and take a multivitamin. N Engl J Med. 1998;338:1060-1061.
FREE FULL TEXT
3. Omenn GS, Beresford SA, Motulsky AG. Preventing coronary heart disease: B vitamins and homocysteine. Circulation. 1998;97:421-424.
FREE FULL TEXT
4. Domagala TB, Undas A, Libura M, Szczeklik A. Pathogenesis of vascular disease in hyperhomocysteinaemia. J Cardiovasc Risk. 1998;5:239-247.
FULL TEXT
| PUBMED
5. Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
FULL TEXT
|
ISI
| PUBMED
6. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the
epidemiologic evidence. Ann Intern Med. 1999;131:363-375.
FREE FULL TEXT
7. Malinow MR. Hyperhomocyst(e)inemia: a common and easily reversible risk factor
for occlusive atherosclerosis. Circulation. 1990;81:2004-2006.
FREE FULL TEXT
8. Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of
published epidemiological studies. J Cardiovasc Risk. 1998;5:229-232.
PUBMED
9. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527.
ABSTRACT
10. Moghadasian MH, McManus BM, Frohlich JJ. Homocyst(e)ine and coronary artery disease: clinical evidence and genetic
and metabolic background. Arch Intern Med. 1997;157:2299-2308.
ABSTRACT
11. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology,
screening, and treatment. Arch Intern Med. 1998;158:1301-1306.
FREE FULL TEXT
12. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for
healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999;99:178-182.
FREE FULL TEXT
13. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular
risk? design of clinical trials to test the homocysteine hypothesis of vascular
disease. J Cardiovasc Risk. 1998;5:249-255.
PUBMED
14. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis
of randomised trials. BMJ. 1998;316:894-898.
FREE FULL TEXT
15. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial
infarction in US physicians. JAMA. 1992;268:877-881.
ABSTRACT
16. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24:704-709.
FREE FULL TEXT
17. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study
with implications regarding prevention. Arch Intern Med. 1998;158:862-867.
FREE FULL TEXT
18. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular
disease mortality in elderly Framingham men and women. Arch Intern Med. 1999;159:1077-1080.
FREE FULL TEXT
19. Bots ML, Launer LJ, Lindemans J, et al. Homocysteine and short-term risk of myocardial infarction and stroke
in the elderly: the Rotterdam Study. Arch Intern Med. 1999;159:38-44.
FREE FULL TEXT
20. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal
women. JAMA. 1999;281:1817-1821.
FREE FULL TEXT
21. Whincup PH, Refsum H, Perry IJ, et al. Serum total homocysteine and coronary heart disease: prospective study
in middle aged men. Heart. 1999;82:448-454.
FREE FULL TEXT
22. Folsom AR, Nieto FJ, McGovern PG, et al. 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. Circulation. 1998;98:204-210.
FREE FULL TEXT
23. Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular
disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901.
FREE FULL TEXT
24. Ubbink JB, Fehily AM, Pickering J, Elwood PC, Vermaak WJ. Homocysteine and ischaemic heart disease in the Caerphilly cohort. Atherosclerosis. 1998;140:349-356.
FULL TEXT
|
ISI
| PUBMED
25. Kark JD, Selhub J, Adler B, et al. Nonfasting plasma total homocysteine level and mortality in middle-aged
and elderly men and women in Jerusalem. Ann Intern Med. 1999;131:321-330.
FREE FULL TEXT
26. Alfthan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to
atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;106:9-19.
FULL TEXT
|
ISI
| PUBMED
27. Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective study of folate and vitamin B6 and risk of myocardial
infarction in US physicians. J Am Coll Nutr. 1996;15:136-143.
ABSTRACT
28. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk
Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953.
FREE FULL TEXT
29. Verhoef P, Hennekens CH, Allen RH, Stabler SP, Willett WC, Stampfer MJ. Plasma total homocysteine and risk of angina pectoris with subsequent
coronary artery bypass surgery. Am J Cardiol. 1997;79:799-801.
FULL TEXT
|
ISI
| PUBMED
30. Reunanen A, Aromaa A, Pyörälä K, Punsar S, Maatela J, Knekt P. The Social Insurance Institution's coronary heart disease study: baseline
data and 5-year mortality experience. Acta Med Scand Suppl. 1983;673:1-120.
PUBMED
31. Aromaa A. Kohonnut Verenpaine ja sen Kansanterveydellinen Merkitys
Suomessa [Epidemiology and Public Health Impact of High Blood Pressure in
Finland]. Helsinki, Finland: Kansaneläkelaitoksen Julkaisuja AL; 1981:17.
32. Heliövaara M, Reunanen A, Aromaa A, Knekt P, Aho K, Suhonen O. Validity of hospital discharge data in a prospective epidemiological
study on stroke and myocardial infarction. Acta Med Scand. 1984;216:309-315.
ISI
| PUBMED
33. Knekt P. Serum Alpha-Tocopherol and the Risk of Cancer. Helsinki, Finland: Publications of the Social Insurance Institution
ML; 1988:83.
34. Ubbink JB, Hayward Vermaak WJ, Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine
levels in human serum. J Chromatogr. 1991;565:441-446.
ISI
| PUBMED
35. Möller J, Rasmussen K, Christensen L. External quality assessment of methylmalonic acid and total homocysteine. Clin Chem. 1999;45:1536-1542.
FREE FULL TEXT
36. Breslow NE, Day NE. Statistical methods in cancer research, volume 1: the analysis of case-control
studies. IARC Sci Publ. 1980;(32):5-338.
37. Cohen J, Cohen P. Applied Multiple Regression/Correlation Analysis
for the Behavioral Sciences. New York, NY: John Wiley & Sons Inc; 1975.
38. Boers GH, Smals AG, Trijbels FJ, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral
occlusive arterial disease. N Engl J Med. 1985;313:709-715.
ABSTRACT
39. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324:1149-1155.
ABSTRACT
40. Graham IM, Daly LE, Refsum HM, et al for the European Concerted Action Project. Plasma homocysteine as a risk factor for vascular disease. JAMA. 1997;277:1775-1781.
ABSTRACT
41. Taylor LM Jr, DeFrang RD, Harris EJ Jr, Porter JM. The association of elevated plasma homocyst(e)ine with progression
of symptomatic peripheral arterial disease. J Vasc Surg. 1991;13:128-136.
FULL TEXT
|
ISI
| PUBMED
42. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary
artery disease. N Engl J Med. 1997;337:230-236.
FREE FULL TEXT
43. Norio R. Diseases in Finland and Scandinavia. In: Rothscild HR, ed. Biocultural Aspects of Disease. Orland, Fla: Academic Press Inc; 1981:358-415.
44. Peltonen L, Jalanko A, Varilo T. Molecular genetics of the Finnish disease heritage. Hum Mol Genet. 1999;8:1913-1923.
FREE FULL TEXT
45. Nygård O, Vollset SE, Refsum H, et al for the Hordaland Homocysteine Study. Total plasma homocysteine and cardiovascular risk profile. JAMA. 1995;274:1526-1533.
ABSTRACT
46. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050.
FREE FULL TEXT
47. Dudman NP. An alternative view of homocysteine. Lancet. 1999;354:2072-2074.
FULL TEXT
|
ISI
| PUBMED
48. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular
disease: causal or casual? Arch Intern Med. 2000;160:422-434.
FREE FULL TEXT
RELATED LETTER
Is Hyperhomocysteinemia a Risk Factor or a Consequence of Coronary Heart Disease?
Marco Cattaneo, Paul Knekt, Antti Reunanen, Georg Alfthan, Markku Heliövaara, Harri Rissanen, Jukka Marniemi, and Arpo Aromaa
Arch Intern Med. 2001;161(21):2628-2629.
EXTRACT
| FULL TEXT
RELATED ARTICLE
Archives of Internal Medicine Reader's Choice: Continuing Medical Education
Arch Intern Med. 2001;161(13):1683-1684.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients
Akalin et al.
Eur J Endocrinol 2008;158:47-52.
ABSTRACT
| FULL TEXT
Relationship Between Homocysteine and Mortality in Chronic Kidney Disease
Menon et al.
Circulation 2006;113:1572-1577.
ABSTRACT
| FULL TEXT
Fractions of Total Plasma Homocysteine in Patients with Ischemic Stroke Before the Age of 55 Years
Sobol et al.
ANGIOLOGY 2005;56:201-209.
ABSTRACT
Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study
Dedoussis et al.
Am. J. Clin. Nutr. 2004;80:849-854.
ABSTRACT
| FULL TEXT
Antibodies to Periodontal Pathogens and Stroke Risk
Pussinen et al.
Stroke 2004;35:2020-2023.
ABSTRACT
| FULL TEXT
The associations between smoking, physical activity, dietary habits and plasma homocysteine levels in cardiovascular disease-free people: the 'ATTICA' study
Chrysohoou et al.
Vasc Med 2004;9:117-123.
|
