(Circulation. 2000;102:852.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Dietary Patterns on Serum Homocysteine
Results of a Randomized, Controlled Feeding Study
From Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Md (L.J.A., E.R.M., T.E.); the Department of Epidemiology and Disease Control, Graduate School of Health Science and Management, Yonsei University, Seoul, Korea (S.H.J.); Cancer Prevention Studies Branch, National Cancer Institute, Bethesda, Md (R.S.-S.); Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, NC (P.-H.L.); and the US Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (M.R.N., J.S.).
Correspondence to Lawrence J. Appel, MD, MPH, Johns Hopkins University, 2024 E Monument St, Suite 2-645, Baltimore, MD 21205-2223. E-mail lappel{at}welch.jhu.edu
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Abstract |
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Background—Elevated blood levels of homocysteine are associated with an increased risk of atherosclerotic cardiovascular disease. Although numerous studies have assessed the impact of vitamin supplements on homocysteine, the effect of dietary patterns on homocysteine has not been well studied.
Methods and Results—During a 3-week run-in, 118 participants were fed a control diet, low in fruits, vegetables, and dairy products, with a fat content typical of US consumption. During an 8-week intervention phase, participants were then fed 1 of 3 randomly assigned diets: the control diet, a diet rich in fruits and vegetables but otherwise similar to control, or a combination diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Between the end of run-in and intervention periods, mean change in homocysteine was +0.46 µmol/L in the control diet, +0.21 µmol/L in the fruits and vegetables diet (P=0.47 compared with control), and -0.34 µmol/L in the combination diet (P=0.03 compared with control, P=0.12 compared with the fruits and vegetables diet). In multivariable regression models, change in homocysteine was significantly and inversely associated with change in serum folate (P=0.03) but not with change in serum vitamin B12 (P=0.64) or pyridoxal 5' phosphate, the coenzyme form of vitamin B6 (P=0.83).
Conclusions—Modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine. These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease.
Key Words: nutrition • risk factors • metabolism
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Asubstantial body of evidence from observational epidemiological studies suggests that homocysteine is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). In 1969, McCully1 first proposed the homocysteine theory of atherosclerosis. He postulated that homocysteine was responsible for the severe atherosclerosis observed in 2 distinct genetic conditions, that is, a rare disorder of vitamin B12 metabolism and classic homocystinuria from homozygous cystathionine ß-synthase deficiency. Since then, >30 observational studies have reported a direct relation between blood levels of homocysteine and ASCVD, including coronary heart disease, cerebrovascular disease, and peripheral vascular disease.2 The relation is progressive and graded through ranges of homocysteine previously considered low or normal.3 4 5 6 7
Among the factors known to influence homocysteine metabolism are several nutrients, including folate, vitamin B6, and vitamin B12. Homocysteine can be remethylated to methionine by methionine synthase in a reaction that requires methyltetrahydrofolate as a methyl donor and vitamin B12 as an enzyme cofactor.8 Alternatively, homocysteine can be transsulfurated to cysteine in reactions that require vitamin B6. In cross-sectional analyses from the Framingham Heart Study, elevated homocysteine was associated with low serum levels and low dietary intake of folate and vitamin B6.9
Several trials have assessed the effects of folic acid, vitamin
B6, and vitamin B12
supplements on homocysteine. In these trials, which typically enrolled
persons with elevated homocysteine, high-dose folic acid supplements
(often providing 
1 mg/d) have reduced fasting levels of
homocysteine.10 Vitamin B6
supplements have had little impact on fasting levels of homocysteine
but reduced the level of homocysteine after methionine
loading.11 Vitamin B12 supplements
have reduced homocysteine in individuals with vitamin
B12 deficiency but have minimal impact in healthy
populations.12 13 However, because of differences in dose
and bioavailability, the effects of vitamins derived from food should
be different from that of high-dose vitamin supplements. For instance,
it is well recognized that folic acid from vitamin supplements is
better absorbed than dietary folate.14
Current dietary guidelines recommend increased consumption of fruits, vegetables, and low-fat dairy products (often milk, consumed with breakfast cereals).15 Unanticipated benefits of these diet recommendations may be an increase in folate, vitamin B6, and vitamin B12 intake and consequently a reduction in homocysteine, which could potentially lower the risk of ASCVD. Cross-sectional analyses from the Framingham Heart Study indicate that frequent consumption of certain foods, particularly, fruits, vegetables, and cereals, is correlated with low plasma levels of homocysteine,16 perhaps as a result of the high folate intake content of these foods. Nonetheless, inferences about causality must be made cautiously because of the potential for residual and uncontrolled confounding from other nutrients and nonnutritional factors.17 One controlled feeding study conducted in a metabolic ward suggested that folate-deficient diets may raise homocysteine, but the diets were unusual because of the artificially low intake of folate, just 25 and 90 µg/d.18
The objective of this study was to describe the effect of specific dietary patterns on fasting levels of total serum homocysteine in the setting of a randomized, controlled feeding study.
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Methods |
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This research was an ancillary study in the Dietary Approaches to Stop Hypertension (DASH) trial, a multicenter trial designed to assess the effects of dietary patterns on blood pressure. This ancillary study, which was conducted at the DASH clinical center at Johns Hopkins, involved only the coauthors rather than the entire DASH collaborative group. Detailed descriptions of the design and methods of DASH19 and of its recruitment procedures20 and main results21 have been published. A local institutional review board approved the trial protocol. Each participant provided written informed consent.
Participants
Trial participants were adults (age 22 years) who were not
taking antihypertensive medication and who had an average
systolic blood pressure <160 mm Hg and average
diastolic blood pressure of 80 to 95 mm Hg. Major
exclusion criteria were poorly controlled diabetes;
hyperlipidemia; cardiovascular event
within 6 months; unwillingness to stop all vitamin and mineral
supplements; use of medications that affect blood pressure; >14
alcoholic drinks per week; and a glomerular filtration rate
of <50 mL/min (as estimated by the Cockroft Gault formula).
Participants were enrolled sequentially into groups. The first group
began controlled feeding in September 1994. The last group ended
feeding in April 1996, before routine fortification of food with
folic acid.
Trial Conduct
After a screening period, eligible and interested participants
began a 3-week run-in period in which they ate the control diet. During
the third week, individuals were randomly assigned to 1 of 3 diets. For
the next 8 weeks, participants ate their randomly assigned diets.
During the last week of run-in and intervention, specimens of serum
were obtained after overnight fasts. Each specimen was collected at
room temperature, allowed to clot over 15 minutes, centrifuged
at 2000g for 15 minutes at 4°C, and then placed in storage
at -70°C until July 1996, when analyses were performed.
Staff blinded to diet assignment collected all follow-up data.
Dietary Patterns
The control diet was relatively low in fruits, vegetables, and
dairy products, with a fat content typical of US consumption. A
second diet was rich in fruits and vegetables but otherwise similar to
the control diet. The combination diet emphasized fruits, vegetables,
and low-fat dairy products. It included whole grains, poultry,
fish, and nuts, and was reduced in fat, red meat, sweets, and
sugar-containing beverages.22
For the 2600-kcal level of the 3 diets, Table 1
displays the macronutrient
profile and the content of folate, vitamin B6,
and vitamin B12 as estimated from database
analyses of the menus using Moore’s Extended Nutrient System
(MENu, Pennington Biomedical Research Center, Baton Rouge, La); the
folate and vitamin B12 content as estimated from
chemical analyses of composited meals; and the average number
of servings per day of selected food groups. For the nutrient estimates
derived from meal composites, a full week cycle of meals at each of 4
calorie levels was composited, stored, and then analyzed for
folate and vitamin B12. For each diet and
nutrient, a standard curve was generated from which the predicted value
at 2600 kcal was estimated.
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Controlled Feeding
On each weekday of the 11-week feeding period, participants ate
either lunch or dinner at the clinical center. After completing the
on-site meal, participants received coolers that contained the other
meals to be consumed off-site. On Fridays, they also received their
weekend meals, all consumed off-site. Self-report of perfect adherence
(no nonstudy foods consumed and all study foods eaten) occurred in
96%, 96%, and 94% of person-days in those assigned to the control,
fruits and vegetables, and combination diets.
A 7-day menu cycle with 21 meals at 4 calorie levels (1600, 2100, 2600, and 3100 kcal) was developed for each diet. Food was prepared in metabolic kitchens, primarily at the Beltsville Human Nutrition Research Center of the US Department of Agriculture, and then served at the Hopkins clinical center. Weight was measured each weekday and was kept stable by adjusting calorie intake.
Laboratory Assays
Total serum homocysteine (free and protein bound) was determined
by high-performance liquid chromatography
according to the method of Araki and Sako23 ; the
between-run coefficient of variation (CV) for this assay was 8%. Serum
folate and vitamin B12 were measured by
radioimmune assay with the use of a kit from Bio-Rad; the between-run
CVs for these assays were 10% and 7%, respectively. Folate in
aliquots of composited meals was measured with the use of a microbial
assay after conjugase treatment.24 Pyridoxal-5'-phosphate
(PLP), the coenzyme form of vitamin B6, was
measured by the tyrosine decarboxylase method, based on principles
described by Shin-Buehring et al25 ; the between-run CV for
this assay was 16%.
Statistical Considerations
Change in fasting levels of total serum homocysteine between the
end of run-in and intervention periods was the primary outcome
variable. The target sample size of 114 at the Hopkins clinical
center was estimated to provide 80% power to detect a mean
between-diet difference of 2 µmol/L in homocysteine.
Analyses were performed on an intention-to-treat basis. For
each outcome variable, run-in values and changes from run-in tended
to be normally distributed; however, several outliers were present.
To minimize the potential influence of these outliers, we displayed
baseline data as medians with interquartile ranges and used robust
regression analyses to test for differences between randomized
groups. In each regression model, the dependent variable was change
from end of run-in to end of intervention. Covariates in each model
were the run-in level of the dependent variable as well as 2
indicator variables corresponding to diet assignment. Trends across
the 3 diets (control, fruits and vegetables, and combination) were
tested in separate models by entering an ordinal variable (0, 1, 2)
corresponding to these 3 diets. To explore the potential influence of
nutrients that affect homocysteine metabolism, we
calculated Spearman correlations between homocysteine and levels of
folate, PLP, and vitamin B12 at end of run-in and
intervention, and between changes in homocysteine and changes in
folate, PLP, and vitamin B12. To assess the
independent association of change in homocysteine with changes in
folate, PLP, and vitamin B12, we
simultaneously entered changes in folate, PLP, and vitamin
B12 in a multivariable regression model.
Analyses were performed with the use of Stata 6.0 and SAS 6.12
software.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Of the 135 who started run-in, 124 (92%) were randomized. Paired specimens of serum, collected at the end of run-in and intervention periods, were available in 118 persons (95% of randomized participants), all of whom completed the 11 weeks of controlled feeding. As displayed in Table 2
,
participants tended to be middle-aged (median age of 49 years, range 23
to 76 years). Approximately half were women, and two thirds came from a
minority background, predominantly black. Before feeding, median folate
intake was 313 µg/d, and few individuals (<20%) were users of
multivitamins or B-complex vitamin supplements.
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Effects of Dietary Patterns on Serum Folate, PLP, and Vitamin
B12
Figures 1, 2, and 3
display mean (95% CI) changes in serum folate, PLP, and vitamin
B12 between the end of run-in and intervention
after adjustment for run-in levels. Mean change in serum folate was
-0.80 µg/L in the control group, +0.10 µg/L in the fruits and
vegetables group (P<0.001 compared with control), and +0.63
µg/L in the combination group (P<0.001 compared with
control, P=0.04 compared with fruits and vegetables). For
serum PLP, mean change was -2.8 nmol/L in the control group, +8.4
nmol/L in the fruits and vegetables group (P<0.001 compared
with control), and +4.3 nmol/L in the combination group
(P=0.03 compared with control, P=0.19 compared
with fruits and vegetables). Mean change in vitamin
B12 was -16 ng/L in the control group, -13 ng/L
in the fruits and vegetables group (P=0.81 compared with
control), and 8.0 ng/L in the combination group (P=0.08
compared with control, P=0.12 compared with fruits and
vegetables).
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Homocysteine
As displayed in Figure 4, mean
within-group change in homocysteine, after adjustment for run-in level,
was +0.46 µmol/L (95% CI -0.04,+0.96) in the control group,
+0.21 µmol/L (95% CI -0.27,+0.69) in the fruits and vegetables
group, and -0.34 µmol/L (95% CI -0.84,+0.16) in combination
group. Between-diet differences were -0.8 µmol/L (95% CI
-1.51, -0.1; P=0.03) comparing control and combination
groups, -0.25 µmol/L (95% CI -0.94, 0.44; P=0.47)
comparing the control group and the fruits and vegetables group, and
-0.55 µmol/L (95% CI -1.24, 0.15; P=0.12)
comparing the fruits and vegetables group and the combination group.
Across the 3 diets, there was a progressive reduction in homocysteine
(P for trend=0.02).
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Correlates of Homocysteine
At the end of run-in, serum homocysteine was significantly and
inversely correlated with serum folate (r=-0.54,
P=0.0001) and vitamin B12
(r=-0.34, P=0.0002) but not PLP
(r=-0.06, P=0.54). An identical pattern of
findings was present in analyses correlating
end-of-intervention homocysteine with end-of-intervention serum
nutrients. However, in analyses correlating change in
homocysteine with changes in nutrients, change in homocysteine was
associated with change in serum folate (r=-0.28,
P=0.002) but not with change in PLP (r=-0.02,
P=0.79) or vitamin B12
(r=-0.12, P=0.21). In regression
analyses that simultaneously adjusted for changes
in serum folate, PLP, and vitamin B12 and for
run-in level of homocysteine, change in serum homocysteine was only
associated with change in folate (Table 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This trial demonstrated that modification of dietary patterns can have substantial effects on fasting levels of serum homocysteine. Specifically, in a population of individuals with high normal blood pressure or stage 1 hypertension, a control diet that was relatively low in fruits, vegetables, and dairy products with a fat content typical of US consumption raised homocysteine. In contrast, the DASH combination diet that was diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat lowered homocysteine. A diet rich in fruits and vegetables but otherwise similar to the control diet had an intermediate effect. Recent data suggest that a 3- to 4-µmol/L reduction in homocysteine should lower vascular disease risk by one third.2 If homocysteine proves to be an independent ASCVD risk factor, then the observed 0.8-µmol/L difference in homocysteine between control and combination diets should lower ASCVD risk by 7% to 9% among persons consuming a typical American diet who subsequently adopt the DASH combination diet.
Among the strengths of this study are high internal and external validity. Follow-up data were collected in 95% of randomized participants. Furthermore, adherence was excellent as indicated by self-reports of food consumption, by changes in serum levels of nutrients (documented in this ancillary study), and by changes in the urinary excretion of electrolytes (documented in the overall trial21 ). We attribute much of our successful follow-up and adherence to the 3-week run-in period that preceded randomization. Also, the study population was demographically heterogeneous. Nearly half of trial participants were women, two thirds were from a minority background, and the age range was broad. In addition, the median level of fasting homocysteine in this trial was similar to corresponding data from a large national survey.26 Finally, the combination diet was broadly consistent with national dietary recommendations.15
Potential limitations of this trial include the duration of feeding (11 weeks), the relatively small sample size (118 persons allocated across 3 groups), and the potential influence of prestudy diets of participants on trial results. On the basis of data from a food frequency questionnaire, prestudy folate intake was >300 µg/d. In the control group, which received a diet with <250 µg/d folate, homocysteine rose between run-in and intervention despite the fact that this group remained on the same diet. One explanation for this finding pertains to the timing of specimen collection; baseline specimens were drawn after just 3 weeks of run-in feeding, a point at which vitamin stores and homocysteine may still have reflected, to some extent, the prestudy dietary intake of participants. The observation that serum folate fell between run-in and intervention in the control group supports the notion that participants had not reached a steady state, at least with respect to folate balance by the end of run-in.
Several aspects of the diets might explain the observed changes in homocysteine, including the gradient across diets. First, dietary folate increased progressively across the diets, with the lowest intake in the control diet and the highest in the combination diet. In exploratory analyses, change in serum folate was significantly and independently correlated with change in homocysteine; no other nutrient was correlated with homocysteine change. Folate-rich foods that might have contributed to the reductions in homocysteine observed in the combination diet include fruits, juices, vegetables, and perhaps dairy products.
Vitamin B12 may also have had a beneficial effect on fasting levels of homocysteine. The combination diet provided more vitamin B12 than either the control diet or the fruits and vegetables diet. Serum vitamin B12 was significantly correlated with homocysteine at the end of both run-in and intervention. However, change in homocysteine was not significantly associated with change in serum vitamin B12. The absence of a relation between change in serum vitamin B12 and change in homocysteine may have resulted from the fact that serum vitamin B12 levels changed minimally over the 8-week intervention period.
Overall, our data suggest that dietary folate intake had a major influence on fasting levels of homocysteine and that vitamin B12 may also have had an effect. Such findings are consistent with the known metabolism of homocysteine,8 with cross-sectional analyses of observational studies,9 and with clinical trials of vitamin supplements.10 11 12 Nonetheless, the trial was designed to test the effects of whole dietary patterns rather than the effects of individual nutrients. The associations of folate and homocysteine, albeit robust, could be distorted (either artificially increased or diminished) from the effects of correlated nutrients, such as vitamin B12, which also affect homocysteine levels. Furthermore, in addition to the well-known determinants of fasting homocysteine, the diets differed in several other aspects, for example, protein intake, which might influence homocysteine metabolism.27
Results of this trial may help to explain the beneficial effects of certain dietary patterns, such as vegetarian diets, which are associated with a reduced risk of ischemic heart disease and stroke.28 29 Although the nutrients responsible for such effects are uncertain, attention has focused on reduced consumption of certain nutrients, such as saturated fat, and increased consumption of potassium, fiber, and naturally occurring antioxidants, such as ß-carotene and lycopene. Results from this study suggest that another mechanism, namely, a reduction in homocysteine, may in part be responsible for the beneficial effects of these diets, many of which are excellent sources of folate.
In summary, modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine. These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease.
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Acknowledgments |
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This study was supported by grants HL-50981 and HL-02642 from the National Heart, Lung, and Blood Institute; grant RR-00722 from the National Center for Research Resources, National Institutes of Health; and contract 53-3K06-01 from the Agricultural Research Service, US Department of Agriculture. We are extraordinarily appreciative of trial participants and of the entire DASH Collaborative Research Group.
Received December 21, 1999; revision received March 4, 2000; accepted March 20, 2000.
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References |
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 C. K. Roberts, R. J. Barnard, R. K. Sindhu, M. Jurczak, A. Ehdaie, and N. D. Vaziri A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression J Appl Physiol, January 1, 2005; 98(1): 203 - 210. [Abstract] [Full Text] [PDF]
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 R. H. Samson, Z. Yungst, and D. P. Showalter Homocysteine, a Risk Factor for Carotid Atherosclerosis, Is Not a Risk Factor for Early Recurrent Carotid Stenosis Following Carotid Endarterectomy Vascular and Endovascular Surgery, July 1, 2004; 38(4): 345 - 348. [Abstract] [PDF]
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X. Gao, O. I. Bermudez, and K. L. Tucker Plasma C-Reactive Protein and Homocysteine Concentrations Are Related to Frequent Fruit and Vegetable Intake in Hispanic and Non-Hispanic White Elders J. Nutr., April 1, 2004; 134(4): 913 - 918. [Abstract] [Full Text] [PDF]
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 J. D. Ard, S. C. Grambow, D. Liu, C. A. Slentz, W. E. Kraus, and L. P. Svetkey The Effect of the PREMIER Interventions on Insulin Sensitivity Diabetes Care, February 1, 2004; 27(2): 340 - 347. [Abstract] [Full Text] [PDF]
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 M. D Tobin, C. Minelli, P. R Burton, and J. R Thompson Commentary: Development of Mendelian randomization: from hypothesis test to 'Mendelian deconfounding' Int. J. Epidemiol., February 1, 2004; 33(1): 26 - 29. [Full Text] [PDF]
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X. Gao, M. Yao, M. A. McCrory, G. Ma, Y. Li, S. B. Roberts, and K. L. Tucker Dietary Pattern Is Associated with Homocysteine and B Vitamin Status in an Urban Chinese Population J. Nutr., November 1, 2003; 133(11): 3636 - 3642. [Abstract] [Full Text] [PDF]
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F. B Hu Plant-based foods and prevention of cardiovascular disease: an overview Am. J. Clinical Nutrition, September 1, 2003; 78(3): 544S - 551. [Abstract] [Full Text] [PDF]
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G. Ravaglia, P. Forti, F. Maioli, A. Muscari, L. Sacchetti, G. Arnone, V. Nativio, T. Talerico, and E. Mariani Homocysteine and cognitive function in healthy elderly community dwellers in Italy Am. J. Clinical Nutrition, March 1, 2003; 77(3): 668 - 673. [Abstract] [Full Text] [PDF]
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 D. Tanne, M. Haim, U. Goldbourt, V. Boyko, R. Doolman, Y. Adler, D. Brunner, S. Behar, and B.-A. Sela Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease Stroke, March 1, 2003; 34(3): 632 - 636. [Abstract] [Full Text] [PDF]
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G. Davey Smith and S. Ebrahim 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., February 1, 2003; 32(1): 1 - 22. [Abstract] [Full Text] [PDF]
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 W. S. Yancy Jr, E. C. Westman, P. A. French, and R. M. Califf Diets and Clinical Coronary Events: The Truth Is Out There Circulation, January 7, 2003; 107(1): 10 - 16. [Full Text] [PDF]
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 U. Lim and P. A. Cassano Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., December 15, 2002; 156(12): 1105 - 1113. [Abstract] [Full Text] [PDF]
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 J. H. Williams and T. C. O'Connell Differential Relations Between Cognition and 15N Isotopic Content of Hair in Elderly People With Dementia and Controls J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2002; 57(12): M797 - 802. [Abstract] [Full Text] [PDF]
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B. J Venn, J. I Mann, S. M Williams, L. J Riddell, A. Chisholm, M. J Harper, and W. Aitken Dietary counseling to increase natural folate intake: a randomized, placebo-controlled trial in free-living subjects to assess effects on serum folate and plasma total homocysteine Am. J. Clinical Nutrition, October 1, 2002; 76(4): 758 - 765. [Abstract] [Full Text] [PDF]
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 K. Robinson Homocysteine and vascular disease Eur. Heart J., October 1, 2002; 23(19): 1482 - 1484. [Full Text] [PDF]
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A. Melse-Boonstra, A. de Bree, P. Verhoef, A. L. Bjorke-Monsen, and W.M. M. Verschuren Dietary Monoglutamate and Polyglutamate Folate Are Associated with Plasma Folate Concentrations in Dutch Men and Women Aged 20-65 Years J. Nutr., June 1, 2002; 132(6): 1307 - 1312. [Abstract] [Full Text] [PDF]
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M.-L. Silaste, M. Rantala, M. Sampi, G. Alfthan, A. Aro, and Y. A. Kesaniemi Polymorphisms of Key Enzymes in Homocysteine Metabolism Affect Diet Responsiveness of Plasma Homocysteine in Healthy Women J. Nutr., October 1, 2001; 131(10): 2643 - 2647. [Abstract] [Full Text] [PDF]
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 M. B. Zemel Calcium Modulation of Hypertension and Obesity: Mechanisms and Implications J. Am. Coll. Nutr., October 1, 2001; 20(90005): 428S - 435. [Abstract] [Full Text]
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L. K. Massey Dairy Food Consumption, Blood Pressure and Stroke J. Nutr., July 1, 2001; 131(7): 1875 - 1878. [Abstract] [Full Text] [PDF]
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