HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lutsey, P. L Articles by Osganian, S. K Search for Related Content PubMed PubMed Citation Articles by Lutsey, P. L Articles by Osganian, S. K Agricola Articles by Lutsey, P. L Articles by Osganian, S. K

Serum homocysteine is related to food intake in adolescents: the Child and Adolescent Trial for Cardiovascular Health ^1,2,3

¹ From the Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN (PLL, LMS, RVL, and LAL); the Clinical Research Program, Children's Hospital Boston, MA (HAF and SKO); the Department of Pediatrics, Harvard Medical School, Boston, MA (HAF and SKO); the New England Research Institutes, Watertown, MA (HAF and SKO); the University of Texas School of Public Health, Houston, TX (DHH); the Department of Biostatistics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (LSW); and the University of California, San Diego, San Diego, CA (MG)

² Supported by grant no. RO1-HL66643 from the National Institutes of Health.

³ Reprints not available. Address correspondence to LM Steffen, Division of Epidemiology and Community Health, University of Minnesota School of Public Health, 1300 South Second Street, Suite 300, Minneapolis, MN 55454. E-mail: steffen{at}epi.umn.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: An understanding of the relation in adolescents between serum homocysteine and foods rich in vitamin B-6, vitamin B-12, and folate is important because high homocysteine concentrations in childhood and adolescence may be a risk factor for later cardiovascular disease. However, little is known about the relation between food intake and homocysteine in adolescents.

Objective: Five years after national folic acid fortification of enriched grain products, cross-sectional relations between food intake and serum homocysteine concentrations were examined in 2695 adolescents [ age: 18.3 (range: 15–20) y] enrolled in the Child and Adolescent Trial for Cardiovascular Health.

Design: A nonfasting blood specimen was analyzed for serum homocysteine, folate, and vitamins B-6 and B-12. Dietary intake was assessed by using a food-frequency questionnaire. Multiple regression analyses were used to evaluate the relation of intakes of whole grains, refined grains, fruit, vegetables, dairy products, red and processed meats, and poultry with serum homocysteine concentrations after adjustment for demographic characteristics, lifestyle factors, and food intake.

Results: Serum homocysteine concentrations were lower with greater intakes of whole grains (P for trend = 0.002), refined grains (P for trend = 0.02), and dairy foods (P for trend <0.001); were higher with greater intake of poultry (P for trend = 0.004); and were not related to intakes of fruit, vegetables, or red or processed meat. After additional adjustment for serum B vitamins, the relations of serum homocysteine with most food groups were attenuated.

Conclusion: These observational findings suggest a beneficial effect of whole-grain, refined-grain, and dairy products on serum homocysteine concentrations in an adolescent population.

Key Words: Homocysteine • serum folate • cardiovascular disease • adolescents • food groups • whole grain

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Cardiovascular disease (CVD) is the leading cause of death in the United States (1). Although the primary cause of this disease is well understood, additional risk factors such as hyperhomocysteinemia are emerging as novel contributors. Several studies suggested that the concentration of plasma homocysteine may be an independent and modifiable risk factor for CVD in adults (2-7). Results from a meta-analysis of 20 prospective studies indicated that, for every 5-µmol/L increase in homocysteine, the odds ratio for risk of ischemic heart disease was 1.32 (95% CI: 1.19, 1.45), and the odds ratio for risk of stroke was 1.59 (95% CI: 1.29, 1.96) (8).

Early stages of atherosclerosis and other physiologic CVD risk factors are present in childhood and adolescence (9-12) and may predict CVD risk in adults (10-14). The distribution of homocysteine is significantly lower in children than in adults (15), but some children may be at risk of high homocysteine concentrations. Several studies showed that elevated homocysteine concentrations are associated with elevated systolic blood pressure (16, 17) and intimal-medial thickness of the coronary artery (18) in children and adolescents.

Folate, vitamin B-6, and vitamin B-12 are essential to the metabolic conversion of homocysteine to either cystathionine or methionine (19). Not surprisingly, epidemiologic evidence from both experimental and observational studies in adult populations showed inverse relations of homocysteine concentrations with nutrient intake and serum concentrations of vitamin B-6, vitamin B-12, and folate (3, 20-25). Multiple feeding trials that evaluated single food groups or fortified food items in relation to homocysteine concentrations in adults found reductions in homocysteine that resulted from greater consumption of fruit and vegetables (26-29), fortified cereals (30, 31), cereals manufactured before national folic acid fortification (29), whole grains (32), and soy products (33-35). However, the relation of major food groups that influence homocysteine concentrations in adolescents has not been explored. Therefore, we examined the relation of food intake to serum concentrations of homocysteine in previously studied adolescents (15, 36) 5 y after national folic acid fortification of enriched-grain products.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study population
The Child and Adolescent Trial for Cardiovascular Health (CATCH study) was a multicenter intervention trial, conducted from 1991 to 1994, to evaluate the effectiveness of an elementary school–based cardiovascular health promotion program in 56 intervention and 40 control schools in California, Louisiana, Minnesota, and Texas (37). More than 5100 ethnically diverse students in grades 3–5 enrolled in the study at baseline, and follow-up surveys were conducted in 1996–1997 (15) and 2000–2001 (36).

These analyses, based on the 2001 follow-up survey data, include 2695 subjects aged 15–20 y, a total that is 53% of the original CATCH cohort. Excluded from this analysis were 60 students without a serum homocysteine value, 41 students with outlying energy intakes, 178 students with other missing data, 229 who did not return consent forms, 177 who dropped out of the study, and 1968 who either moved out of the survey area or did not participate in the 2000–2001 follow-up survey.

Written assent and written informed consent was obtained from all participants and their parents, respectively. The CATCH study was approved by the institutional review boards at all study sites.

Measurements
All data were collected by trained, certified CATCH study staff at school sites. The Health Behavior Survey was used to collect information from students about behaviors, attitudes, knowledge, and environmental influences with respect to nutrition, physical activity, smoking, alcohol, and health.

Height without shoes was measured by using a portable stadiometer (Perspective Enterprises, Portage, MI), and weight was measured by using the SECA Integra 815 portable scale (SECA, Rumilly, France). Body mass index (BMI) was calculated as weight (in kg) divided by height (in m²).

Venipuncture
Nonfasting blood samples were obtained via venipuncture while the child was seated. The venipuncture procedure and processing have been reported (15). Total homocysteine was measured by using the fluorimetric method, except that 20% methanol in buffer B was used in the HPLC procedure (38). Serum vitamin B-12 and folate were measured by using a solid-phase, no-boil radioimmunoassay in a commercial kit (Diagnostic Productions Corp, Los Angeles, CA; 39, 40). Vitamin B-6 was analyzed by using a radioassay kit (ALPCO, Windham, NH) that measures the conversion of titrated tyrosine to tyramine by the vitamin B-6–dependent enzyme tyrosine decarboxylase (41).

Diet assessment
Diet was assessed through self-administration of the 149-item Youth/Adolescent Questionnaire. This instrument has been validated in youth and adolescent populations through the administration of 2 food-frequency questionnaires and three 24-h recalls over a period of 1 y in a sample of 261 children (42).

Foods were aggregated into 10 groups: whole grains, refined grains, fruit, vegetables, dairy, red and processed meat, poultry, fish, eggs, and nuts. The whole- and refined-grain groups were classified according to previously developed procedures (43). Whole-grain ready-to-eat breakfast cereals contained 25% whole grain or bran by weight, as ascertained from the package label or from records shared by cereal manufacturing companies. Other food items classified as whole-grain included cooked oatmeal, dark bread, brown rice, other grains (eg, bulgur, kasha, and couscous), bran, wheat germ, and popcorn. Refined-grain food items included ready-to-eat breakfast cereals with < 25% whole grain or bran, white bread, bagels, rolls, muffins, pasta, white rice, pancakes and waffles, doughnuts, cakes, cookies, and pie. The fruit group included 10 types of fruit (juices were not included because of their high sugar content); the vegetable group included 23 vegetables and legumes; the dairy group included milk, cheese, yogurt, and ice cream products; the meat group included red and processed meat; the poultry group included chicken or turkey as a main dish and chicken nuggets; the egg group included eggs and eggs that were used to make French toast; the nut group included peanuts and peanut butter; and the fish group included 3 fish-containing items.

Statistical analysis
Analyses were conducted with SAS statistical software (version 8.2; SAS Institute, Cary, NC). The sampling design was considered in all statistical models, and the school was treated as a random effect within the site. Because of their highly skewed distributions, serum concentrations of homocysteine, folate, vitamin B-6, and vitamin B-12 were log transformed, and values are reported as geometric means (95% CIs). Mean (±SD) and frequencies of demographics, nutrient intakes, food intakes, and other clinical characteristics were calculated, with adjustments for age, race, energy intake, and site (CA, LA, MN, or TX). We used t tests to evaluate sex differences for continuous variables. Spearman partial correlations adjusted for age, sex, race, site, and energy intake were calculated to describe the relation between serum concentrations and nutrient intakes. The correlations for folate, vitamin B-6, and vitamin B-12 were 0.42 (P < 0.001), 0.39 (P < 0.001), and 0.13 (P < 0.001), respectively.

The whole-grain, refined-grain, fruit, vegetable, dairy, poultry, and meat groups were categorized into quintiles; the lowest quintile of intake for each food group formed the reference category for that food group. Eggs, nuts, and fish were categorized into tertiles, because of the low level of consumption. Linear regression was used to evaluate the relation between serum homocysteine as the dependent variable to the quintiles of food intake as the independent variables. Other models were developed to evaluate the relations of the serum vitamin B variables to food intake.

Three models were developed to evaluate the relation between serum variables and food intake. Model 1, which ascertained whether these relations were independent of demographic characteristics, was adjusted for age, sex, race, site, and energy intake. Model 2, which further adjusted for the lifestyle factors of smoking (yes if 1 cigarette/wk or no), vitamin supplement use (yes or no), BMI, and intake of the following food groups: whole grains, refined grains, fruit, vegetables, dairy, red or processed meat, and poultry. To ascertain whether homocysteine was related to food intake independent of biologic mechanisms, further adjustment in model 3 included serum folate and vitamins B-6 and B-12. Finally, interaction terms were included in the models to ascertain whether differences—including differences in vitamin supplement use and sex—existed between subgroups. However, because interaction terms were not significant, the models were adjusted for these covariates.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The cohort of 2695 participants had a mean age of 18 y, and 51% were female. More than 70% of the participants were white, 12% were black, 10% were Hispanic, and 4% were classified as "other." Demographic characteristics and mean dietary intakes of the boys and girls are shown in Table 1. The clinical characteristics of participants by sex are shown in Table 2. Compared with the girls, the boys had significantly (P < 0.001 for all) higher serum concentrations of homocysteine (6.4 and 5.1 µmol/L, respectively), vitamin B-6 (44.2 and 36.2 nmol/L, respectively), and vitamin B-12 (460 and 428 pg/mL, respectively) and significantly (P < 0.001) lower serum concentrations of folate (18.9 and 20.4 ng/mL, respectively).

Table 3

Serum folate concentrations were positively associated with dietary intakes of whole grains (P for trend < 0.001), refined grains (P for trend < 0.001), fruit (P for trend = 0.008), and dairy (P for trend < 0.001) and inversely associated with dietary intakes of red and processed meat (P = 0.008), but they were not associated with the intake of vegetables or poultry (data not shown). Serum vitamin B-6 was positively associated with intakes of whole grains (P for trend < 0.001), fruit (P for trend = 0.04), vegetables (P for trend = 0.002), dairy (P for trend < 0.001), and poultry (P for trend = < 0.001) but not with those of refined grains or red and processed meat (data not shown). In comparison, serum vitamin B-12 was positively associated with intakes of whole grain (P for trend = 0.001), dairy (P for trend < 0.001), and red and processed meat (P for trend = 0.001) but not with intakes of refined grains, fruit, vegetables, or poultry (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Few, if any, observational studies of adolescents have examined the relation between food intakes and homocysteine concentrations. In this cohort of 2695 adolescents, boys had significantly greater mean homocysteine concentrations than did girls—6.4 and 5.1 µmol/L, respectively. After control for demographic and lifestyle factors and other food group intakes, there was an inverse dose-response relation between homocysteine and intakes of whole-grain foods, refined-grain foods, and dairy products. However, poultry intake was positively associated, and intakes of fruit, vegetables, red and processed meat, eggs, nuts, and fish were not associated with serum homocysteine.

Consistent with our study results, clinical studies conducted in adults also show an inverse relation between whole-grain intake and homocysteine concentrations. Several food-based feeding trials have shown reductions in homocysteine that resulted from greater consumption of fortified cereals (30, 31), cereals manufactured before national folic acid fortification (29), whole grains (32), and a combination diet rich in fruit, vegetables, and low-fat dairy products but low in saturated fat (44). Another study found elevated homocysteine concentrations after the cessation of habitual consumption of breakfast cereals (30).

The inverse relation between homocysteine and whole-grain intake and the positive relation between serum folate and whole-grain intake found in this study are consistent with the biological mechanisms by which homocysteine is created and with the results from previously conducted food-based feeding trials (29-31). In our analyses, the relation between whole grain and homocysteine was attenuated after adjustment for serum folate, which suggested that folate drives the relation between whole grain and homocysteine. Whole grains are inherently rich sources of folate (25), which acts in the conversion of homocysteine to methionine (19) and has been found to lower homocysteine in numerous nutrient-based feeding trials (32).

Since folic acid fortification of enriched-grain products was mandated by the US government in 1998, observational studies have shown higher concentrations of serum folate in adults (45, 46) and children (37). Adults enrolled in the Framingham Offspring Study had mean serum folate concentrations after the fortification of grain products (1997-1998) that were significantly higher than those measured before folic acid fortification (1995-1996); the prevalence of adults with a high serum homocysteine concentration was 50% lower in the later than in the earlier group (47).

Serum homocysteine concentrations measured in CATCH study participants before and after fortification showed that extra dietary folate increased serum folate (from 37.8 to 43.5 nmol/L) in this cohort of adolescents and may offset an age-related increase in homocysteine (37). Our finding that refined-grain consumption was negatively associated with homocysteine concentrations and positively associated with serum folate concentrations is also consistent with our a priori hypotheses. Furthermore, the relation between refined grains and homocysteine was attenuated after adjustment for folate and vitamin B-12 concentrations, which supports the notion that folic acid fortification has a beneficial effect on homocysteine concentrations (47).

Inverse associations between homocysteine and fruit and vegetable intakes have been observed in numerous epidemiologic studies (26-29, 44). However, no association was observed between homocysteine and fruit or vegetable intake in the current study, even though fruit and vegetables are good sources of folate. The range of fruit and vegetable intakes in the adolescents enrolled in the current study may have been too limited for observation of a significant association, even though fruit and vegetable intakes were positively associated with serum folate concentrations.

Dairy products are a rich source of vitamin B-12, which is necessary for the metabolic conversion of homocysteine to methionine (19). In epidemiologic studies, dairy products have been found to have a modest effect on homocysteine (48), as has vitamin B-12, especially when considered together with folate (4, 20, 21, 49). There is evidence that a low serum vitamin B-12 concentration may prevent an optimal response to folate (50, 51).

Poultry intake has not previously been associated with homocysteine concentrations. However, most studies did not examine poultry independent of other meats. Poultry contains relatively high concentrations of methionine, which is the sole dietary precursor of homocysteine (52). Red and processed meats were not related to the homocysteine concentration in the current study, a finding that is consistent with previous research (48, 53).

The major strength of the current study is the large number of adolescents who continue to participate in the CATCH study. One limitation of the current study is that the analysis included only 53% of the original CATCH study cohort. Nevertheless, although a direct comparison has not been conducted, there is little reason to believe that the relation between food intake and serum homocysteine concentrations would differ significantly between those who participated in the current study and those who did not. The dietary intake was assessed by using a food-frequency questionnaire, an instrument that does not capture information about fortified foods (42). We do not know how much folate was in the form of folic acid rather than as natural folates. Consequently, we were unable to adjust for differences in bioavailability. After ascertaining that there was no modifying effect of supplement use on the relation between food intake and homocysteine concentrations, we adjusted for vitamin supplement use in the regression models. However, we do know that dietary folate affected homocysteine concentrations, because relations between diet and homocysteine remained significant after adjustment for multivitamin intake. In addition, although the food-frequency questionnaire was not initially designed to differentiate whole-grain from refined-grain foods, any misclassification of foods would have resulted in an attenuated association. For example, hot cereals were classified as a refined-grain food; therefore, any association would be underestimated, because some whole-grain hot cereals (other than oatmeal, a whole-grain cereal that was queried about separately) were actually included in the food group labeled "refined grains." It is also possible that dietary intakes may be confounded, because eating behaviors tend to cluster. For example, other studies report that greater whole-grain consumption is related to healthier eating behaviors, including lower red meat intake and greater fruit and vegetable intakes (43). To control for this phenomenon, we adjusted our statistical models for the other food groups, as in model 2; however, it is possible that residual confounding remains. Our findings are consistent with the recommendations in the 2005 edition of Dietary Guidelines for Americans (54) to eat a variety of foods, including grains, fruit, vegetables, and dairy products.

	ACKNOWLEDGMENTS

 
The authors thank the other investigators, the staff, and the participants of the CATCH study for their valuable contributions.

PLL, LMS, and SKO designed the study. PLL and LMS conducted the analysis and wrote the manuscript. PLL, LMS, HAF, DHH, RVL, LAL, LSW, MZ and SKO made substantial conceptual contributions and revisions. None of the authors had a personal or financial conflict of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep 2003;52:1–86.[Medline]
2. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359–64.[Abstract/Free Full Text]
3. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62.[Medline]
4. Siri PW, Verhoef P, Kok FJ. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr 1998;17:435–41.[Abstract/Free Full Text]
5. Evans RW, Shaten J, Hempel JD, Cutler JA, Kuller LH. Homocystiene and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Aterioscler Thromb Vasc Biol 1997;17:1947–53.[Abstract/Free Full Text]
6. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526–33.
7. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281:1817–21.[Abstract/Free Full Text]
8. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202.[Abstract/Free Full Text]
9. McGill HC. Morphologic development of the atherosclerotic plaque. In: Lauer RM, Shekelle RB, eds. Childhood prevention of atherosclerosis and hypertension. New York: Raven Press, 1980:41–50.
10. Morrison JA, Glueck CJ. Pediatric risk factors for adult coronary heart disease: primary atherosclerosis prevention. Cardiovasc Rev Rep 1981;2:1269–81.
11. McGill HC Jr, McMahan CA. Starting earlier to prevent heart disease. JAMA 2003;290:2320–1 (editorial).[Free Full Text]
12. Newman WP III, Freedman DS, Voors AW, et al. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study. N Engl J Med 1986;314:138–44.
13. Voors AW, Webber LS, Berenson GS. Time course studies of blood pressure in children: the Bogalusa Heart Study. Am J Epidemiol 1979;109:320–34.[Abstract/Free Full Text]
14. Lauer RM, Lee J, Clarke WR. Factors affecting the relationship between childhood and adult cholesterol levels. Pediatrics 1988;82:309–18.[Abstract/Free Full Text]
15. Osganian SK, Stampfer MJ, Spiegelman D, et al. Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. JAMA 1999;281:1189–96.[Abstract/Free Full Text]
16. Tonstad S, Refsum H, Ueland PM. Association between plasma total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia. Circulation 1997;96:1803–8.[Abstract/Free Full Text]
17. Kahleova R, Palyzova D, Zvara K, et al. Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hyperten 2002;15:857–64.[Medline]
18. Tonstad S, Joakimsen O, Stensland-Bugge E, et al. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects. Arterioscler Thromb Vasc Biol 1996;16:984–91.[Abstract/Free Full Text]
19. Rees M, Rodgers G. Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993;71:337–59.[Medline]
20. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693–8.[Abstract/Free Full Text]
21. Kluijtmans LA, Young IS, Boreham CA, et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 2003;101:2483–8.[Abstract/Free Full Text]
22. McKinley MC, McNulty H, McPartlin J, et al. Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am J Clin Nutr 2001;73:759–64.[Abstract/Free Full Text]
23. Bates CJ, Pentieva KD, Prentice A. An appraisal of vitamin B6 status indices and associated confounders, in young people aged 4–18 years and in people aged 65 years and over in two national British surveys. Public Health Nutr 1999;2:529–35.[Medline]
24. Robinson K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate: common and independent reversible risk factors for coronary artery disease. Circulation 1995;92:2825–30.[Abstract/Free Full Text]
25. Wardlaw GM, Kessel M. Perspectives in nutrition. 5th ed. Boston, MA: McGraw-Hill, 2002.
26. Broekmans WM, Klopping-Ketelaars IA, Schuurman CR, et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578–83.[Abstract/Free Full Text]
27. Brouwer IA, van Dusseldorp M, West CE, et al. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 1999;129:1135–9.[Abstract/Free Full Text]
28. Silaste ML, Rantala M, Alfthan G, Aro A, Kesaniemi YA. Plasma homocysteine concentration is decreased by dietary intervention. Br J Nutr 2003;89:295–301.[Medline]
29. Tucker KL, Selhub J, Wilson PW, Rosenberg IH. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr 1996;126:3025–31.[Abstract/Free Full Text]
30. Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009–15.[Abstract/Free Full Text]
31. Riddell LJ, Chisholm A, Williams S, Mann JI. Dietary strategies for lowering homocysteine concentrations. Am J Clin Nutr 2000;71:1448–54.[Abstract/Free Full Text]
32. Jang Y, Lee JH, Kim OY, Park HY, Lee SY. Consumption of whole grain and legume powder reduces insulin demand, lipid peroxidation, and plasma homocysteine concentrations in patients with coronary artery disease: randomized controlled clinical trial. Arterioscler Thromb Vasc Biol 2001;21:2065–71.[Abstract/Free Full Text]
33. Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K. Soy product intake is inversely associated with serum homocysteine level in premenopausal Japanese women. J Nutr 2003;133:797–800.[Abstract/Free Full Text]
34. Jenkins DJ, Kendall CW, Jackson CJ, et al. Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women. Am J Clin Nutr 2002;76:365–72.[Abstract/Free Full Text]
35. Tonstad S, Smerud K, Hoie L. A comparison of the effects of 2 doses of soy protein or casein on serum lipids, serum lipoproteins, and plasma total homocysteine in hypercholesterolemic subjects. Am J Clin Nutr 2002;76:78–84.[Abstract/Free Full Text]
36. Osganian SK, Feldman HA, Hoelscher DM, et al. Serum homocysteine in US adolescents before and after universal folate supplementation. Circulation 2003;107:e7026 (abstr).
37. Luepker RV, Perry C, McKinlay SM, et al. Outcomes of a field trial to improve children's dietary patterns and physical activity. JAMA 1996;275:768–76.[Abstract/Free Full Text]
38. Vester B, Rasmussen K. High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem 1991;29:549–54.[Medline]
39. McNeely M. Folate assay. In: Kaplan LA, Pesce AJ, eds. Clinical chemistry. St Louis, MO: CV Mosby, 1984:1402–6.
40. El Shami AS, Durham AP. More on vitamin B12 results as measured with boil and no-boil kits. Clin Chem 1983;29:2115–6.[Free Full Text]
41. Shin YS, Rasshofer R, Friedrich B, Endres W. Pyridoxal-5-phosphate determination by a sensitive micromethod in human blood, urine, and tissues; its relation to cystathioninuria in neuroblastoma and biliary atresia. Clin Chim Acta 1983;127:77–85.[Medline]
42. Rockett HR, Breitenbach M, Frazier AL, et al. Validation of a youth/adolescent food frequency questionnaire. Prev Med 1997;26:808–16.[Medline]
43. Steffen LM, Jacobs DR Jr, Stevens J, Shahar E, Carithers T, Folsom AR. Associations of whole-grain, refined-grain, and fruit and vegetable consumption with risks of all-cause mortality and incident coronary artery disease and ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2003;78:383–90.[Abstract/Free Full Text]
44. Appel LJ, Miller ER, Jee SH, et al. Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation 2000;102:852–7.[Abstract/Free Full Text]
45. Lawrence JM, Petitti DB, Watkins M, Umekubo MA. Trends in serum folate after food fortification. Lancet 1999;354:915–6.[Medline]
46. Lawrence JM, Chiu V, Petitti DB. Fortification of foods with folic acid. N Engl J Med 2000;343:970 (letter).[Free Full Text]
47. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449–54.[Abstract/Free Full Text]
48. Ganji V, Kafai MR. Frequent consumption of milk, yogurt, cold breakfast cereals, peppers, and cruciferous vegetables and intakes of dietary folate and riboflavin but not vitamins B-12 and B-6 are inversely associated with serum total homocysteine concentrations in the US population. Am J Clin Nutr 2004;80:1500–7.[Abstract/Free Full Text]
49. Brattstrom LE, Israelsson B, Jeppsson JO. Folic acid—an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 1988;48:215–21.[Medline]
50. Guttormsen A, Ueland P, Nesthus I. Determinants and vitamin responsiveness of intermediate hyperhomocysteiniemia (³40 umol/L). The Hordaland Homocysteine Study. J Clin Invest 1996;98:2174–83.
51. Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr 1996;126:1276S–80S.[Abstract/Free Full Text]
52. Finkelstein JD, Martin JJ. Homocysteine. Int J Biochem Cell Biol 2000;32:385–9.[Medline]
53. Diakoumopoulou E, Tentolouris N, Kirlaki E, et al. Plasma homocysteine levels in patients with type 2 diabetes in a Mediterranean population: relation with nutritional and other factors. Nutr Met Cardiovasc Dis 2005;15:109–17.
54. US Department of Agriculture. Dietary guidelines for Americans. Internet: www.health.gov/dietaryguidelines/dga2005/document/ (accessed 25 April 2005).

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lutsey, P. L Articles by Osganian, S. K Search for Related Content PubMed PubMed Citation Articles by Lutsey, P. L Articles by Osganian, S. K Agricola Articles by Lutsey, P. L Articles by Osganian, S. K