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(Stroke. 1995;26:1166-1170.)
© 1995 American Heart Association, Inc.

Articles

Serum Folate and Risk for Ischemic Stroke

First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study

Wayne H. Giles, MD, MS; Steven J. Kittner, MD, MPH; Robert F. Anda, MD, MS; Janet B. Croft, PhD Michele L. Casper, PhD

From the Cardiovascular Health Studies Branch, Division of Chronic Disease Control and Community Intervention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Ga (W.H.G., R.F.A., J.B.C., M.L.C.); and the Department of Epidemiology and Preventive Medicine, the Department of Neurology, and the Stroke Epidemiology Unit, University of Maryland School of Medicine, Baltimore (S.J.K.).

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose A serum folate concentration 9.2 nmol/L has been associated with elevated levels of plasma homocyst(e)ine. Elevated homocyst(e)ine levels have been associated with ischemic stroke in case-control studies; however, the results from prospective studies have been equivocal. We investigated whether a folate concentration 9.2 nmol/L was associated with ischemic stroke in a national cohort.

Methods We used data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (n=2006). Cox proportional hazards analyses were used to adjust for differences in follow-up time and covariates. During the 13-year follow-up, 98 ischemic strokes occurred.

Results After adjusting for age, race, sex, education, diabetes, history of heart disease, systolic blood pressure, body mass index, hemoglobin level, cigarette smoking, and alcohol intake, participants with a folate concentration 9.2 nmol/L were at slightly increased risk for ischemic stroke (relative risk [RR], 1.37; 95% confidence interval [CI], 0.82 to 2.29). There was a folate-race interaction (P=.11 for interaction term). Whites with a folate concentration 9.2 nmol/L had a relative risk of 1.18 (95% CI, 0.67 to 2.08), whereas blacks had a relative risk of 3.60 (95% CI, 1.02 to 12.71).

Conclusions These findings suggest that a folate concentration 9.2 nmol/L may be a risk factor for ischemic stroke, especially in blacks. However, given the small number of stroke events, additional studies are needed to assess the role of folate in the epidemiology of ischemic stroke.

Key Words: epidemiology • folic acid • racial differences • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A number of epidemiological studies have noted an association between increased levels of homocyst(e)ine and atherosclerotic disease, suggesting that an elevated homocyst(e)ine level may be an independent risk factor for atherosclerosis.^{1 2 3 4 5 6 7 8 9 10} Elevated homocyst(e)ine levels can be due to genetic disorders or deficiencies of folate, vitamin B₆, or vitamin B₁₂.^{11 12} Approximately two thirds of the cases of elevated homocyst(e)ine may be associated with low or moderate levels of folate, vitamin B₆, or vitamin B₁₂.¹¹

Several case-control studies have noted an association between elevated homocyst(e)ine levels and stroke.^{13 14 15 16 17} However, these studies cannot rule out the possibility that the elevated homocyst(e)ine levels were a consequence of the stroke. Two studies have examined the association between homocyst(e)ine and stroke in a prospective manner. Verhoef et al,¹⁸ using data from the Physician's Health Study, reported that men with an elevated homocyst(e)ine level were at slightly increased risk for ischemic stroke (relative risk [RR], 1.2; 95% confidence interval [CI], 0.7 to 2.0) after adjusting for covariates. Conversely, Alfthan et al¹⁹ were unable to find any association between homocyst(e)ine and stroke in a prospective study of Finnish adults from North Karelia (men: RR, 1.01; 95% CI, 0.92 to 1.10; women: RR, 1.10; 95% CI, 0.98 to 1.24).

Homocyst(e)ine levels were not obtained on the participants in the First National Health and Nutrition Examination Survey (NHANES I). However, serum folate levels were obtained on a subset of NHANES I participants. A folate concentration 9.2 nmol/L has previously been associated with an elevated homocyst(e)ine level.¹¹ Therefore, the objectives of this study were to use data from the NHANES I Epidemiologic Follow-up Study, 1987 (NHEFS) to determine whether participants with a serum folate concentration 9.2 nmol/L were at increased risk for ischemic stroke after adjusting for covariates. The data were also used to determine whether the association between folate and ischemic stroke was modified by sex or race.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
NHANES I was conducted by the National Center for Health Statistics from 1971 through 1975 to collect health-related information on a probability sample of the US civilian noninstitutionalized population. To increase the sample size in select subgroups, the survey oversampled the elderly, persons living in poverty areas, and women of childbearing age.^{20 21 22}

The NHEFS was jointly initiated by the National Center for Health Statistics and the National Institutes of Health. The objective of the NHEFS was to follow up the 14 407 examinees in NHANES I who were between 25 and 74 years of age at the time of that survey.²³ Data collection for this analysis included follow-up through 1987 and tracing all NHANES I participants for morbidity and mortality.²⁴ Because of the low incidence of stroke among young participants, only individuals older than 35 years of age were included in this analysis. Of the 2167 participants between 35 and 74 years of age who had serum folate levels obtained, the following groups were excluded: participants who at the baseline interview reported an affirmative response to the question "Has a doctor ever told you that you had a stroke?" (40); participants whose race was neither black nor white (17); participants who lacked information concerning sociodemographic or stroke risk factors (50); and participants who lacked follow-up information (54). Thus, of the initial sample of 2167 people, this analysis included 2006 (93%).

Definition of Incident Ischemic Stroke
Ischemic stroke events were determined by hospital record or death certificate diagnosis of one of the following International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes: 433 to 434 (cerebral occlusion) or 436 to 438 (ill-defined stroke). There were 98 ischemic strokes during the 13-year follow-up period.

Study Variables
Serum folate determinations were obtained on study participants during the NHANES I baseline examination in a mobile examination center. The details of the procedures used for blood collection and specimen storage, biochemical assays to determine folate status, and procedures for ensuring quality control and obtaining informed consent have been published elsewhere.^{20 25} The risk for ischemic stroke was compared between persons with a serum folate concentration 9.2 nmol/L and those with folate concentration >9.2 nmol/L. Serum folate was dichotomized because there is evidence of a threshold effect in the relationship between folate and homocyst(e)ine.¹¹ The folate level 9.2 nmol/L was chosen because this level is associated with an elevated homocyst(e)ine level.¹¹

Potential confounders in the association between serum folate and ischemic stroke included age, sex, race (black, white), education (<12 years, 12 years, >12 years), systolic blood pressure, diabetes, history of heart disease, body mass index (weight [kg]/height [m²]), serum hemoglobin level, cigarette smoking (never, former, current), and alcohol intake (none, 1 to 7 drinks per week, >7 drinks per week). All measures were obtained during the NHANES I baseline interview. The race of the respondent was determined by observation as "white," "Negro," or "other."²⁶ If the appropriate category was unclear, the respondent was asked to define his/her race. Diabetes mellitus was determined by patient self-report or a diagnosis made by one of the NHANES I examining physicians. A history of heart disease was defined as a history of myocardial infarction, congestive heart failure, or angina, as determined either by patient self-report or a diagnosis made by one of the NHANES I examining physicians.

Statistical Analysis
One-way ANOVA and ² tests were used to test differences in selected characteristics between groups defined by either serum folate concentration or presence of ischemic stroke. Because the interval of follow-up varied among survey participants, Cox proportional hazards analysis was used to estimate the relative risk for ischemic stroke among participants with a folate concentration 9.2 nmol/L compared with participants with a concentration >9.2 nmol/L. The Cox proportional hazards assumptions for each explanatory variable were assessed with the SAS procedure LIFETEST.²⁷ We calculated 95% CIs using a Taylor series approximation for the SE of the RR.²⁸ To determine whether the race or sex of the participant modified the risk of a folate concentration 9.2 nmol/L, an interaction term between serum folate and race or sex was entered into a Cox proportional hazards model that adjusted for potentially confounding variables.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study population included 356 people (17.7%) with a folate concentration 9.2 nmol/L. Participants with a folate concentration 9.2 nmol/L were younger and more likely to be men, black, current smokers, and to consume one or more drinks of alcohol per week (Table 1). There was no significant difference in years of education, systolic blood pressure, diabetes, history of heart disease, or body mass index according to folate status.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Study Participants Stratified by Serum Folate Concentration, NHANES I Epidemiologic Follow-up Study, 1987

As expected, persons who suffered a stroke were more likely to be older, men, and less educated compared with people who had not suffered a stroke (Table 2). Mean systolic blood pressure was significantly higher in the stroke patients compared with people who did not suffer a stroke (151 mm Hg versus 133 mm Hg, respectively). The prevalence of diabetes and history of heart disease was also higher in the stroke patients.

View this table: [in this window] [in a new window]   Table 2. Characteristics of Study Participants Stratified by Ischemic Stroke Status, NHANES I Epidemiologic Follow-up Study, 1987

The proportion of adults who suffered an ischemic stroke was 5.34% among persons with a serum folate concentration 9.2 nmol/L and 4.79% among persons with a folate concentration >9.2 nmol/L (Table 3). After we adjusted for differences in age, race, sex, education, diabetes, history of heart disease, systolic blood pressure, body mass index, hemoglobin level, cigarette smoking, and alcohol intake, participants with a serum folate concentration 9.2 nmol/L were at slightly increased risk for ischemic stroke (RR, 1.37; 95% CI, 0.82 to 2.29) (Table 3).

View this table: [in this window] [in a new window]   Table 3. Relative Risk of Developing Ischemic Stroke Among Study Participants With and Without a Folate Level 9.2 nmol/L, NHANES I Epidemiologic Follow-up Study, 1987

The association between folate and ischemic stroke was not modified by sex (Table 4). The RR for ischemic stroke among participants with a folate concentration 9.2 nmol/L was 1.64 for women (95% CI, 0.75 to 3.60) and 1.22 for men (95% CI, 0.62 to 2.38; P=.57 for folate-sex interaction). However, the association between folate and ischemic stroke was modified by race. Among whites the RR was 1.18 (95% CI, 0.67 to 2.08), whereas among blacks the RR was 3.60 (95% CI, 1.02 to 12.71; P=.11 for folate-race interaction). Of the 11 strokes that occurred in the black participants, four occurred in blacks with a folate concentration 9.2 nmol/L.

View this table: [in this window] [in a new window]   Table 4. Relative Risk of Developing Ischemic Stroke Among Persons With and Without a Folate Level 9.2 nmol/L Stratified by Sex and Race, NHANES I Epidemiologic Follow-up Study, 1987

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The results of this analysis suggest that a serum folate concentration 9.2 nmol/L may slightly increase the risk for ischemic stroke. Although two prospective studies have examined the association between homocyst(e)ine and stroke,^{18 19} this is the first study to examine the association between folate and ischemic stroke. The finding that a folate concentration 9.2 nmol/L may slightly increase the risk for ischemic stroke is similar to that of Verhoef et al¹⁸ on the association between homocyst(e)ine and ischemic stroke. However, since the results in the current study were not statistically significant, the results are also consistent with no association existing between serum folate and ischemic stroke.

The increased risk for stroke was particularly pronounced in blacks. If the association between homocyst(e)ine and ischemic stroke is stronger in blacks than whites, or if a folate level 9.2 nmol/L is more likely to lead to an elevated homocyst(e)ine level in blacks than whites, this might explain the interaction between folate and race in the risk for ischemic stroke. However, the folate-race interaction should be interpreted with caution. There were only 11 strokes in blacks, and only four strokes occurred in blacks with a folate concentration 9.2 nmol/L. Additional prospective studies in biracial populations are needed to assess the possibility of an interaction between folate status and race in the risk for ischemic stroke.

A folate concentration 9.2 nmol/L has been associated with an increased homocyst(e)ine level.¹¹ Data from the Framingham Study indicate that approximately two thirds of elevated homocyst(e)ine levels may be secondary to low or moderate levels of folate, vitamin B₆, or vitamin B₁₂.¹¹ The proportion of elevated homocyst(e)ine levels that may be secondary to low or moderate levels of folic acid alone is not clear. However, limited data suggest that the administration of folic acid is associated with the reduction of elevated homocyst(e)ine levels.¹⁷ Whether lowering homocyst(e)ine levels can reduce the risk for ischemic stroke needs to be determined.

Several mechanisms have been postulated for the association between homocyst(e)ine and stroke. The oxidation of homocyst(e)ine may result in the formation of free radicals and hydrogen peroxide, damaging the endothelial lining^{29 30} and promoting the oxidation of low-density lipoprotein cholesterol.^{31 32} Both of these processes are precursors to atherosclerosis. In addition, homocyst(e)ine and its metabolites can affect blood coagulation by increasing factor V activity,³³ platelet thromboxane production,³⁴ and platelet aggregation³⁵ and by decreasing the activation of protein C.³⁶ Thus, elevated levels of homocyst(e)ine may not only be associated with an increased risk for atherosclerosis but also an increased risk for thrombosis.

If the association between folate and ischemic stroke is not mediated through homocyst(e)ine, it may be mediated through other stroke risk factors. However, the present analysis revealed no association between folate and education, blood pressure, diabetes, history of heart disease, or body mass index. A folate concentration 9.2 nmol/L was associated with being male, black, a current smoker, and alcohol intake, all of which increased the risk for stroke. However, after we adjusted for these potentially confounding variables, the association between folate and ischemic stroke remained, making it unlikely that the increased risk could be solely mediated through these factors.

Cigarette smoking and the consumption of alcohol may cause a depression in serum folate levels and a subsequent elevation in homcyst(e)ine concentration.^{37 38} Therefore, adjusting for these potentially confounding variables could have removed some of the "effect" of folic acid on stroke. However, the analysis was repeated after cigarette smoking and alcohol consumption were excluded from the Cox proportional hazards model, and the risk estimates did not change substantially.

Because of data from the Framingham Study,¹¹ serum folate concentration was dichotomized at the level 9.2 nmol/L. Additional analyses were performed in which we divided serum folate into quintiles and used serum folate as a continuous variable. In both of these types of analysis serum folate was not associated with ischemic stroke.

Although the results from the present analysis were not statistically significant, the analysis was limited by both sample size and number of stroke events. Given the sample size of 2006 people and 98 strokes, there was only a 26% power to detect an RR of 1.37 with a type I error of less than .05. To achieve a 90% power, the analysis would have required a sample size of more than 13 000 people. Other studies reporting a modest association between homocyst(e)ine and ischemic stroke¹⁸ may also have experienced a similar low statistical power to detect a statistically significant relationship.

This analysis is subject to several limitations. First, stroke risk factor data included only information collected during the NHANES I baseline interview. Change in risk factor status during the 13-year follow-up period could not be considered. The resultant misclassification of risk factor status would tend to attenuate the association between folate and ischemic stroke. Furthermore, not all individuals with a folate concentration 9.2 nmol/L will have elevated homocyst(e)ine levels. Therefore, using a folate concentration 9.2 nmol/L to define stroke risk will cause some misclassification in stroke risk. This misclassification could further attenuate any potential association between folate and ischemic stroke. Second, the data on ischemic stroke ascertainment were limited to diagnoses abstracted from hospital admissions and death certificates. If participants with a folate concentration 9.2 nmol/L were more likely to be hospitalized for stroke, this might bias the results. However, ascertainment bias seems unlikely since it is improbable that folate status would influence the probability of hospitalization. Third, because of the correlation between many indexes of nutritional status, the association between folate and ischemic stroke may actually reflect an association between poor nutritional status and ischemic stroke. However, studies that have assessed the association between poor nutritional status and stroke have failed to show an association. For example, White et al³⁹ were unable to find any association between serum potassium and ischemic stroke in the NHEFS. Fourth and most important, the number of stroke events was small. Only 19 strokes occurred in survey participants with a folate concentration 9.2 nmol/L; of these, only four occurred in black participants. Given the limited sample size and stroke event rate, the results should be viewed with caution and need to be confirmed in additional studies.

Despite these limitations, the results from the current analysis suggest that a folate concentration 9.2 nmol/L may slightly increase the risk for ischemic stroke. Additional studies are needed to confirm this association and, if confirmed, to determine whether the increased intake of folic acid can reduce the risk for ischemic stroke.

	Acknowledgments

 
This study was supported by the Clinical Stroke Research Center at the University of Maryland funded by the National Institutes of Neurological Disorders and Stroke (NS16332-11) (Dr Kittner).

	Footnotes

 
Reprint requests to Wayne H. Giles, MD, Cardiovascular Health Studies Branch, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Mailstop K-47, Atlanta, GA 30341-3724.

Received March 17, 1995; revision received April 21, 1995; accepted April 21, 1995.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
1. Jacobsen DW. Cardiovascular disorders (risk assessment). Clin Chem. 1993;65:367R-373R.

2. Eristland J, Arnesen H, Seljeflot I, Abdelnoor M, Gronseth K, Berg K, Malinow MR. Influence of serum lipoprotein(a) and homocyst(e)ine levels on graft patency after coronary artery bypass grafting. Am J Cardiol. 1994;74:1099-1102. [Medline] [Order article via Infotrieve]

3. Kang S, Wonk PWK, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279-298. [Medline] [Order article via Infotrieve]

4. Malinow MR. Hyperhomocyst(e)inemia a common and easily reversible risk factor for occlusive atherosclerosis. Circulation. 1990;81:2004-2006. [Free Full Text]

5. Malinow MR, Nieto J, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults: the Atherosclerosis Risk in Communities Study. Circulation. 1993;87:1107-1113. [Abstract/Free Full Text]

6. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmenn D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881. [Abstract/Free Full Text]

7. Molgaard J, Malinow MR, Lassvik C, Holm AC, Upson B, Olsson AG. Hyperhomocyst(e)inaemia: an independent risk factor for intermittent claudication. J Intern Med. 1992;231:273-279. [Medline] [Order article via Infotrieve]

8. Taylor LM, DeFrang RD, Harris EJ, Porter JM. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg. 1991;13:128-136. [Medline] [Order article via Infotrieve]

9. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324:1149-1155. [Abstract]

10. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993;57:47-53. [Abstract/Free Full Text]

11. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocyst(e)ine in an elderly population. JAMA. 1993;270:2693-2698. [Abstract/Free Full Text]

12. Brattstrom LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984;15:1012-1016. [Abstract/Free Full Text]

13. Boers GHJ, Smals AGH, Tribels FJM, Fowler B, Bakkeren JA, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive artery disease. N Engl J Med. 1985;313:709-715. [Abstract]

14. Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, Pat de Garmo ANP. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke. 1990;21:572-576. [Abstract/Free Full Text]

15. Brattstrom L, Lindgren A, Israelsson B, Malinow MR, Norving B, Upson B, Hamfelt A. Hyperhomocysteinaemia in stroke: prevalence, cause and relationships to type of stroke and stroke risk factors. Eur J Clin Invest. 1992;22:214-221. [Medline] [Order article via Infotrieve]

16. Araki A, Sako Y, Fukushima Y, Matsumoto M, Asada T, Kita T. Plasma sulfhydryl-containing amino acids in patients with cerebral infarctions and in hypertensive subjects. Atherosclerosis. 1989;79:139-146. [Medline] [Order article via Infotrieve]

17. Brattstrom L, Israelsson B, Norving B, Bergqvist D, Thorme J, Hultberg B, Hamfelt A. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease: effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990;81:51-60. [Medline] [Order article via Infotrieve]

18. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke. 1994;25:1924-1930. [Abstract]

19. Alfthan G, Pekkanen J, Juhiainen M, Pitkaniemi J, Karvonen M, Tuomilehto J, Salonen JT, Ehnholm C. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;106:9-19. [Medline] [Order article via Infotrieve]

20. National Center for Health Statistics. Plan and Operation of the Health and Nutrition Examination Survey, United States, 1971-1973: Part A: Development, Plan and Operation. Rockville, Md: US Dept of Health, Education, and Welfare; 1977. US Dept of Health, Education, and Welfare publication HRA77-310. Vital and Health Statistics, Series 1, No. 10a.

21. National Center for Health Statistics. Plan and Operation of the Health and Nutrition Examination Survey, United States, 1971-1973: Part B: Data Collection Forms of the Survey. Rockville, Md: US Dept of Health, Education, and Welfare; 1977. US Dept of Health, Education, and Welfare publication HRA77-1310. Vital and Health Statistics, Series 1, No. 10b.

22. National Center for Health Statistics. Plan and Operation of the NHANES I Augmentation Survey of Adults 25-74 Years, United States, 1974-1975. Hyattsville, Md: National Center for Health Statistics; 1978. Vital and Health Statistics, Series 1, No. 10c.

23. Cornoni-Huntley J, Barbano HE, Brody JA, Cohen B, Feldman JJ, Kleinman JC, Madans J. National Health and Nutrition Examination I: Epidemiologic Follow-up Survey. Public Health Rep. 1983;98:245-251. [Medline] [Order article via Infotrieve]

24. Madans JH, Cox CS, Kleinman JC, Makuc D, Feldman JJ, Finucane FF, Barbano HE, Cornoni-Huntley J. Ten years after NHANES: report of initial follow-up, 1982-1984. Pub Health Rep. 1986;101:465-474. [Medline] [Order article via Infotrieve]

25. US Department of Health, Education, and Welfare. HANES I Hematology and Clinical Chemistry Procedures Developed or Utilized by the Centers for Disease Control, Bureau of Laboratories, 1971-1975. Hyattsville, Md: National Center for Health Statistics; 1979.

26. Hadden W, Maurer K, Collins E, Stanton ES, Blodget D, Weinberger RM. Documentation for Medical History (Ages 111-711) Data Tape. Hyattsville, Md: National Center for Health Statistics; 1989. Catalog No. 4081, Health and Nutrition Examination Survey 1971-1975.

27. SAS Institute Inc. SAS/STAT User's Guide, Version 6. 4th ed. Cary, NC: SAS Institute Inc; 1989.

28. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research. New York, NY: Van Nostrand Reinhold; 1982:351.

29. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaus J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest. 1988;81:466-474.

30. Starkebaum G, Harlan JM. Endothelial cell injury due to cooper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest. 1986;77:1370-1376.

31. Parthasarathy S. Oxidation of low density lipoproteins by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochim Biophys Acta. 1987;917:337-340. [Medline] [Order article via Infotrieve]

32. Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987;262:10098-10103. [Abstract/Free Full Text]

33. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest. 1986;77:1909-1916.

34. Graeber JE, Slott JH, Ulane RE, Schulman JD, Stuart MJ. Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res. 1982;16:490-493. [Medline] [Order article via Infotrieve]

35. McCully KS, Carvalho AC. Homocysteine thiolactone, N-homocysteine thiolactonyl retinamide, and platelet aggregation. Res Commun Chem Pathol Pharmacol. 1987;56:349-360. [Medline] [Order article via Infotrieve]

36. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood. 1990;75:895-901. [Abstract/Free Full Text]

37. Piyathilake CJ, Macaluso M, Hine RJ, Richards EW, Krumdieck CL. Local and systemic effects of cigarette smoking on folate and vitamin B-12. Am J Clin Nutr. 1994;60:559-566. [Abstract/Free Full Text]

38. Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics. Alcohol Clin Exp Res. 1993;17:687-689. [Medline] [Order article via Infotrieve]

39. White LR, Losonczy KG, Wolf P. Cerebrovascular disease. In: Cornoni-Huntley J, Huntley RR, Feldman JJ, eds. Health Status and Well-being of the Elderly: National Health and Nutrition Examination I: Epidemiologic Follow-up Survey. New York, NY: Oxford University Press, Inc; 1990:115-135.

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				N. K. Kim, B. O. Choi, W. S. Jung, Y. J. Choi, and K. G. Choi Hyperhomocysteinemia as an independent risk factor for silent brain infarction Neurology, December 9, 2003; 61(11): 1595 - 1599. [Abstract] [Full Text] [PDF]

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				L. A. Bazzano, J. He, L. G. Ogden, C. Loria, S. Vupputuri, L. Myers, P. K. Whelton, and S. E. Kasner Dietary Intake of Folate and Risk of Stroke in US Men and Women: NHANES I Epidemiologic Follow-Up Study * Editorial Comment: NHANES I Epidemiologic Follow-Up Study Stroke, May 1, 2002; 33(5): 1183 - 1189. [Abstract] [Full Text] [PDF]

				M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 6 - 13. [Abstract] [Full Text] [PDF]

				K. M Koehler, R. N Baumgartner, P. J Garry, R. H Allen, S. P Stabler, and E. B Rimm Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use Am. J. Clinical Nutrition, March 1, 2001; 73(3): 628 - 637. [Abstract] [Full Text] [PDF]

				C. M. Loria, D. D. Ingram, J. J. Feldman, J. D. Wright, and J. H. Madans Serum Folate and Cardiovascular Disease Mortality Among US Men and Women Arch Intern Med, November 27, 2000; 160(21): 3258 - 3262. [Abstract] [Full Text] [PDF]

				I. I. Kruman, C. Culmsee, S. L. Chan, Y. Kruman, Z. Guo, L. Penix, and M. P. Mattson Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity J. Neurosci., September 15, 2000; 20(18): 6920 - 6926. [Abstract] [Full Text] [PDF]

				L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [Abstract] [Full Text] [PDF]

				P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset The controversy over homocysteine and cardiovascular risk Am. J. Clinical Nutrition, August 1, 2000; 72(2): 324 - 332. [Abstract] [Full Text] [PDF]

				J. W. Eikelboom, E. Lonn, J. Genest Jr., G. Hankey, and S. Yusuf Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence Ann Intern Med, September 7, 1999; 131(5): 363 - 375. [Abstract] [Full Text] [PDF]

				M. C. Verhaar, R. M. F. Wever, J. J. P. Kastelein, D. van Loon, S. Milstien, H. A. Koomans, and T. J. Rabelink Effects of Oral Folic Acid Supplementation on Endothelial Function in Familial Hypercholesterolemia : A Randomized Placebo-Controlled Trial Circulation, July 27, 1999; 100(4): 335 - 338. [Abstract] [Full Text] [PDF]

				I. A Brouwer, M. van Dusseldorp, C. M. Thomas, M. Duran, J. G. Hautvast, T. K. Eskes, and R. P. Steegers-Theunissen Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial Am. J. Clinical Nutrition, January 1, 1999; 69(1): 99 - 104. [Abstract] [Full Text] [PDF]

				C. D. A. Stehouwer, M. P. Weijenberg, M. van den Berg, C. Jakobs, E. J. M. Feskens, and D. Kromhout Serum Homocysteine and Risk of Coronary Heart Disease and Cerebrovascular Disease in Elderly Men : A 10-Year Follow-Up Arterioscler Thromb Vasc Biol, December 1, 1998; 18(12): 1895 - 1901. [Abstract] [Full Text] [PDF]

				W. H. Giles, J. B. Croft, K. J. Greenlund, E. S. Ford, and S. J. Kittner Total Homocyst(e)ine Concentration and the Likelihood of Nonfatal Stroke : Results From the Third National Health and Nutrition Examination Survey, 1988–1994 Stroke, December 1, 1998; 29(12): 2473 - 2477. [Abstract] [Full Text] [PDF]

				P. W. Siri, P. Verhoef, and F. J. Kok Vitamins B6, B12, and Folate: Association with Plasma Total Homocysteine and Risk of Coronary Atherosclerosis J. Am. Coll. Nutr., October 1, 1998; 17(5): 435 - 441. [Abstract] [Full Text] [PDF]

				F. Zhang, A. Slungaard, G. M. Vercellotti, and C. Iadecola Superoxide-dependent cerebrovascular effects of homocysteine Am J Physiol Regulatory Integrative Comp Physiol, June 1, 1998; 274(6): R1704 - R1711. [Abstract] [Full Text] [PDF]

				R. W. Evans, B. J. Shaten, J. D. Hempel, J. A. Cutler, and L. H. Kuller Homocyst(e)ine and Risk of Cardiovascular Disease in the Multiple Risk Factor Intervention Trial Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 1947 - 1953. [Abstract] [Full Text]

				S. Evers, H.-G. Koch, K.-H. Grotemeyer, B. Lange, T. Deufel, and E.-B. Ringelstein Features, Symptoms, and Neurophysiological Findings in Stroke Associated With Hyperhomocysteinemia Arch Neurol, October 1, 1997; 54(10): 1276 - 1282. [Abstract] [PDF]

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