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Background: High concentrations of plasma homocysteine (Hcyp) have been associated with increased risk of cardiovascular diseases. Hcyp can be decreased by remethylation to methionine, which uses folate or betaine as a donor of the methyl group. Objectives: To evaluate the intake of betaine and choline and its relation to homocysteine in residents of the city of São Paulo. Methods: Data from 584 individual, of both sexes, from the population-based study ISA-SP 2008. Geometric averages of Hcyp were analyzed according to choline and betaine intake tertiles and trend test was applied. Results: The study analyzed 584 individuals: 222 (38.0%) men and 362 (62.0%) women, mean age 55.0 ± 19.0 years. The prevalence of hyperhomocysteinemia was higher among men (28.0%), the elderly (21.0%) and those with lower household income (21.0%). Approximately 31.0% of individual with hyperhomocysteinemia presented folate deficiency (<7.5 nmol/L) and 26.0% presented vitamin B12 deficiency (<200 pmol/L). There was a decrease in the geometric means of homocysteine according to an increase in betaine tertiles in both sexes, adults, normal and in all categories of education. Choline was related to Hcyp in both sexes, higher household income individuals, non-smokers and alcohol consumers. Conclusions: This study suggests the importance of betaine intake due to its inverse relationship with the concentration of Hcyp in adults and elderly in the city of São Paulo. Choline played a protective role in specific subgroups of the population. Abstract
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61
DOI: 10.5935/2359-4802.20150009
Internacional Journal of Cardiovascular Sciences. 2015; 1(1):61-69
Mailing address: Raíssa do Vale Cardoso Lopes
Av. Dr. Arnaldo, 715 - Cerqueira César - 01246-904 - São Paulo, SP - Brazil
E-mail: raissa.vale.lopes@usp.br
Betaine and Choline Intakes are Related to Total Plasma Homocysteine:
Health Survey of São Paulo, Brazil
Raíssa do Vale Cardoso Lopes
1
, Michelle Alessandra de Castro
2
, Valéria Troncoso Baltar
3
,
Dirce Maria Lobo Marchioni
2
, Regina Mara Fisberg
2
1
Universidade de São Paulo - Faculdade de Saúde Pública - Departamento de Nutrição - Programa de Pós-graduação (Mestrado) - São
Paulo, SP - Brazil
2
Universidade de São Paulo - Faculdade de Saúde Pública - Departamento de Nutrição - São Paulo, SP - Brazil
3
Universidade Federal Fluminense - Instituto de Saúde Coletiva - Departamento de Epidemiologia e Bioestatística - Niterói, RJ - Brazil
Background: High concentrations of plasma homocysteine (Hcyp) have been associated with increased risk of
cardiovascular diseases. Hcyp can be decreased by remethylation to methionine, which uses folate or betaine as
a donor of the methyl group.
Objectives: To evaluate the intake of betaine and choline and its relation to homocysteine in residents of the city
of São Paulo.
Methods: Data from 584 individual, of both sexes, from the population-based study ISA-SP 2008. Geometric
averages of Hcyp were analyzed according to choline and betaine intake tertiles and trend test was applied.
Results: The study analyzed 584 individuals: 222 (38.0%) men and 362 (62.0%) women, mean age 55.0 ± 19.0 years.
The prevalence of hyperhomocysteinemia was higher among men (28.0%), the elderly (21.0%) and those with
lower household income (21.0%). Approximately 31.0% of individual with hyperhomocysteinemia presented
folate deciency (<7.5 nmol/L) and 26.0% presented vitamin B12 deciency (<200 pmol/L). There was a decrease
in the geometric means of homocysteine according to an increase in betaine tertiles in both sexes, adults, normal
and in all categories of education. Choline was related to Hcyp in both sexes, higher household income individuals,
non-smokers and alcohol consumers.
Conclusions: This study suggests the importance of betaine intake due to its inverse relationship with the
concentration of Hcyp in adults and elderly in the city of São Paulo. Choline played a protective role in specic
subgroups of the population.
Keywords: Betaine; Choline; Homocysteine; Diet; Cardiovascular diseases
Abstract
Manuscript received on December 17, 2014; approved on January 11, 2015; revised on January 15, 2015.
ORIGINAL MANUSCRIPT
Introduction
High plasma homocysteine concentrations have been
associated with increased risk for developing
cardiovascular diseases, especially atherosclerosis and
coronary ischemia events
1-4
.
A biologically plausible mechanism for the
atherothrombotic effect of homocysteine refers to its
autoxidation with subsequent generation of hydrogen
peroxide, damaging the endothelial cells and causing the
proliferation of smooth muscle cells of vessels
4,5
. High
concentrations of homocysteine can still activate
inflammatory responses involved in the etiology of
atherosclerosis
6
.
Reduction in homocysteine concentrations may occur
through remethylation to methionine, using folate or
betaine as donors of the methyl group. Betaine obtained
directly from the diet or from the oxidation of its
precursor, choline, can remethylate homocysteine via the
enzyme betaine-homocysteine methyltransferase
(BHMT). The activity of BHMT becomes crucial when
folate availability is reduced due to low intake or low
use of the folate pool by organism
7
. Besides the folate,
deciencies of vitamins B6 and B12 may also contribute
62
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
ABBREVIATIONS AND
ACRONYMS
Hcyp – plasma homocysteine
BHMT – betaine-homocysteine
methyltransferase
HPLC – high-performance
liquid cromatrography
to the elevation of plasma homocysteine
8
,
since they are interrelated compounds
in the homocysteine metabolic cycle.
Regardless of folate and vitamins B6 and
B12, higher dietary intakes of choline
and betaine were associated with lower
concentrations of homocysteine
9
.
The main dietary sources of choline are
animal products such as red meat, eggs
and poultry; while betaine is obtained mainly from
grains
10
.
Considering the importance of betaine and choline in
homocysteine metabolism and the lack of studies
dedicated to investigating its use in humans, this study
aims to assess the intake of these nutrients and to
investigate its relationship with plasma homocysteine in
adults and elderly in São Paulo.
Methods
The data used in this study came from the cross-sectional
population-based “ISA - Capital 2008”, with a probabilistic
sample of residents from the urban area of the city of São
Paulo, Brazil1
11
.
Adults (20-59 years) and elderly (≥60 years)
of both sexes with full food consumption data were selected
for this study (n=584).
The Research Ethics Committee from Faculdade de Saúde
Pública da Universidade de São Paulo approved the
study under no. 2001 and all participants signed an
Informed Consent Form.
Data collection for the study ISA-Capital was conducted
from 2008 to 2011. Demographic, socioeconomic and
lifestyle variables (dietary intake, physical activity,
smoking and intake of alcohol) were obtained at home
through questionnaires given by trained interviewers.
In the next stage, blood samples were collected,
anthropometric measurements were taken (weight,
height and waist circumference) and the blood pressure
of the same individuals assessed in the rst stage of the
study was checked. For this, there was another home
visit by a trained nurse, following standardized
procedures developed specically for the study. The
second dietary measure was collected one week before
the home visit, by telephone interview and in order to
investigate the association of dietary variables with
anthropometric and biochemical variables.
Diet analysis
We obtained the rst measure of food consumption by
a 24-hour food recall applied by the Multiple Pass Method
developed by the US Department of Agriculture, in which
data collection is structured around ve steps
12
. This
method helps the individuals record any food and drink
consumed the day before the interview and report them
in detail, reducing errors in dietetic measures
13
.
In the second measure of dietary intake, the 24-hour food
recall was applied by telephone by Nutrition students,
according to the procedures of the Automated Multiple
Pass Method (AMPM), also divided into ve stages,
including direct typing in the program Nutrition Data
System for Research. Students were trained to use the
program and used an explanatory manual to assist them
in collecting data.
The study employed the statistical modeling technique
Multiple Source Method (MSM), an online platform to
estimate the usual intake of nutrients based on
consumption data from two 24-hour recalls. MSM
provides estimates of usual intake through the
combination of likelihood and amount of consumption
14
.
Biomarkers
Blood collection was performed at home by a trained
nursing professional after the participant’s 12-hour
fasting period. About 10
ml of blood was collected by
venipuncture in two dry tubes centrifuged at 1
448 rpm
for 15
min at room temperature. After centrifugation,
plasma samples were stored at -80 ºC.
For homocysteine measurement, the high-performance
cromatrography method (HPLC) was used. Serum
vitamin B6 analysis was performed by HPLC
15
while
serum folate and vitamin B6 levels were measured by
the electrochemiluminescence method
16-18
.
For the classification of individuals with
hyperhomocysteinemia,
the following cutoff points were
adopted: Hcyp ≥12 mmol/l, for individuals aged 15-65 years,
and Hcyp ≥16
mmol/l, for those aged> 65 years.
Statistical analysis
For each individual, the average intake of choline and
betaine was calculated and measured by both 24-hour
recalls. The intake of these nutrients has been described
as median due to the lack of normal distribution of
choline and betaine revealed by the Skewness-Kurtosis
test.
63
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
The geometric averages of plasma homocysteine were
analyzed according to tertiles of choline and betaine
intake and nonparametric trend test was conducted. Stata
version 12.0 was employed, considering a level of
signicance of 5%.
The relative contribution (RC) of food to betaine and
choline was calculated according to Block
20
, in which:
This study describes only the foods that contributed 1%
or more betaine and choline in the diet of individuals in
the study.
Results
The study analyzed 584 individuals: 222 (38.0%) men and
362 (62.0%) women, of which 285 (49.0%) are elderly. The
mean age of the study population was 55.0±19.0 years; the
average age of the non-elderly group was 39.0±12.0 years,
while the average age of the elderly was 71.0±7.0 years.
Table 1 shows the prevalence of hyperhomocysteinemia
according to demographic, anthropometric and lifestyle
variables. The prevalence of hyperhomocysteinemia was
statistically higher in males (28.0%) compared to women
(10.0%) (p<0.001). In addition, hyperhomocysteinemia
was more prevalent in the elderly (21.0%) and in
individuals with household income equal or below the
minimum wage (21.0%).
People with hyperhomocysteinemia showed signicant
differences in the consumption of energy and nutrients
compared to individuals without hyperhomocysteinemia,
except for carbohydrates, dietary folate equivalent and
synthetic folate (Table 2). For biochemical variables,
median serum folate, vitamin B6 and vitamin B12 were
shown statistically lower in individuals with
hyperhomocysteinemia. Furthermore, about 31.0% of
individuals hyperhomocysteinemia presented folate
deciency (<7.5 nmol/L) and 26.0% had a vitamin B12
deciency (<200 pmol/L).
Table 1
Plasma homocysteine concentrations in the population studied, according to demographic, socioeconomic and lifestyle
variables
Variables
Plasma homocysteine
p
Normal
a
High
b
n
c
% n
c
%
Sex
Male 159 71.6 63 28.4
<0.001
Female 325 89.8 37 10.2
Age group
Non-elderly 259 86.6 40 13.4
0.014
Elderly 225 78.9 60 21.1
Nutritional status
Low weight 44 84.6 8 15.4
0.648
Eutrophy 191 83.0 39 17.0
Overweight 106 86.9 16 13.1
Obesity 126 81.3 29 18.7
Education
≤8 years 297 82.0 65 18.0
0.541
≥9 years 184 84.0 35 16.0
Income
≤1 minimum wage 196 79.0 52 21.0
0.034
>1 minimum wage 288 85.7 48 14.3
Smoking
Former smoker 116 78.9 31 21.1
0.211Smoker 86 81.1 20 18.9
Non smoker 282 85.2 49 14.8
Alcoholism
Yes 212 81.5 48 18.5
0.442
No 272 84.0 52 16.0
a
Average Hcyp: 9.4 µmol/l (n=484)
b
Average Hcyp: 20.4 µmol/l (n=100)
c
Individuals with incomplete data have been excluded
x 100
Total Choline or Betaine from all foods
Total Choline or Betaine from the diet i
RC =
64
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
Table 3 shows the geometric averages of plasma
homocysteine according to tertiles of betaine intake for
demographic, socioeconomic and lifestyle variables.
There was a decrease in the geometric averages of plasma
homocysteine according to an increase in consumption
tertiles of betaine for all variable categories considered,
except for the elderly, non-normal individuals, non-
smoking individuals, individuals with household income
above one minimum wage and non-alcoholics. As for
choline, the relationship with plasma homocysteine levels
was observed in both sexes, individuals with household
income above one minimum wage, non-smokers and
alcohol consumers (Table 4).
Table 5 shows the foods that mostly contribute to the intake
of betaine and choline, and average consumption in grams
of food and nutrients. About 69.0% of the total dietary
betaine was provided by the intake of 10 foods, including
white bread (21.0%), cereals and pasta (15.0%) and biscuits
(13.0%). As for choline, 60.0% of this nutrient was provided
by 10 foods. Of these, beef (20.0%), poultry (11.0%) and
eggs (6.0%) had the largest contribution percentages.
Table 2
Dietary and biochemical variables in the population studied according to plasma homocysteine concentration
Variables
Plasma homocysteine
p
a
Normal High
Median IQ Median IQ
Dietary
Energy (kcal) 1
644 645.4 1
494 705.9 0.037
Carbohydrate (g) 202.0 74.4 188.8 74.4 0.066
Proteins (g) 71.3 29.9 61.2 32.2 0.005
Lipids (g) 55.2 30.0 50.8 29.4 0.046
Betaine (mg) 118.1 62.1 104.9 46.1 0.001
Choline (mg) 243.1 111.7 219.7 116.0 0.008
Methionine (g) 1.6 0.7 1.4 0.7 0.006
Dietary folate equiv. (DFE - µg) 492.6 176.9 488.0 176.9 0.307
Natural folate (µg) 172.9 64.3 167.9 63.9 0.036
Synthetic folate (µg) 187.8 92.6 190.1 93.2 0.811
Vitamin B6 (mg) 1.4 0.6 1.3 0.6 0.005
Vitamin B12 (µg) 3.9 2.5 3.5 2.4 0.024
Biochemical
variables
Serum folate (hmol/L) 9.7 5.5 7.3 5.5 <0.001
Serum vitamin B6 (hmol/l) 53.7 28.5 71.8 29.9 <0.001
Serum vitamin B12 (rmol/l) 275.0 162.0 211.5 126.0 <0.001
a
U-Mann Whitney test; IQ - interquartile interval
65
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
Table 3
Geometric averages of plasma homocysteine of the population studied according to tertiles of betaine intake
Variables
Betaine (mg)
n T1 T2 T3 p-value
a
Sex
Male 222 12.1 10.6 9.3 0.001
Female 362 8.3 8.1 7.2 0.019
Age group
Non-elderly 299 9.0 8.8 7.8 0.014
Elderly 285 12.4 11.1 10.5 0.121
Nutritional status
Low weight 52 9.4 9.5 9.1 0.328
Eutrophy 230 10.0 9.2 8.1 0.002
Overweight 122 8.9 8.7 7.8 0.264
Obesity 155 9.5 9.5 8.2 0.131
Education
≤8 years 362 10.1 8.9 8.2 0.028
≥9 years 219 9.2 9.4 8.2 0.016
Income
≤1 minimum wage 248 9.7 9.1 7.7 0.008
>1 minimum wage 336 9.6 9.3 8.4 0.057
Smoking
Former smoker 147 11.1 9.3 8.1 0.024
Smoker 106 10.4 8.4 8.9 0.043
Non smoker 331 8.8 9.4 7.9 0.056
Alcoholism
Yes 260 10.8 9.2 8.6 0.001
No 324 8.8 9.3 7.7 0.132
a
non-parametric trend test
Table 4
Geometric averages of plasma homocysteine of the population studied according to tertiles of choline intake
Variables
Choline (mg)
n T1 T2 T3 p-value
a
Sex
Male 222 12.7 10.5 9.6 0.005
Female 362 8.7 7.7 6.9 <0.001
Age group
Non-elderly 299 8.9 8.5 8.1 0.164
Elderly 285 12.2 11.2 10.3 0.708
Nutritional status
Low weight 52 9.4 9.1 9.5 0.908
Eutrophy 230 9.5 9.5 8.1 0.072
Overweight 122 9.0 7.9 8.5 0.212
Obesity 155 10.3 8.3 8.5 0.309
Education
≤8 years 362 9.7 9.2 8.5 0.085
≥9 years 219 9.8 8.8 8.3 0.061
Income
≤1 minimum wage 248 9.2 9.3 8.1 0.186
>1 minimum wage 336 10.2 8.7 8.5 0.024
Smoking
Former smoker 147 10.1 9.8 8.5 0.327
Smoker 106 9.9 8.6 9.4 0.935
Non smoker 331 9.5 8.8 7.9 0.004
Alcoholism
Yes 260 10.5 9.1 8.8 0.048
No 324 9.2 8.6 7.8 0.060
a
non-parametric trend test
66
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
Discussion
This study is the rst to investigate the relationship
between dietary betaine and choline and plasma
homocysteine in a population-based sample in individuals
from São Paulo.
The higher prevalence of hyperhomocysteinemia in men
and in the elderly conrms the results also obtained by
Jacques et al.
21
in the Framingham cohort study.
According to Neves et al.
22
, sex and age are the main
physiological factors related to hyperhomocysteinemia.
Table 5
Average consumption of foods of higher distribution for betaine and choline in the population studied
Food group % Average consumption (g) Nutrient (mg)
Betaine
White breads 20.59 71 51.02
Cereals and pasta 15.49 202 116.07
Biscuit 12.69 39 69.97
Whole meal breads 5.80 59 67.69
Mate tea 4.80 297 220.52
Beer 3.11 849 68.75
Beef 2.34 120 14.60
Beetroot 1.93 51 77.07
Beetroot 1.38 101 7.04
Pizza 1.30 176 55.78
Choline
Beef 19.73 120 104.75
Poultry 10.52 101 81.61
Eggs 6.28 64 140.21
Milk 5.45 202 31.24
Ox liver 4.08 158 695.37
Beans 3.24 74 27.44
Fish 2.39 221 142.12
Cakes
a
2.33 55 88.26
Sausage 2.20 84 50.42
Beer 1.84 849 84.03
French bread roll 1.71 72 10.66
a
no topping or lling
Men have, on average, plasma homocysteine levels 21.0%
higher than women. In addition, older individuals tend
to have higher circulating levels of homocysteine both
resulting from aging
19
and deficiency of vitamins,
especially vitamin B12
23
.
Most dietary variables presented different intake means
according to plasma homocysteine concentrations. Lower
median intakes of choline, betaine, natural folate and
vitamins B6 and B12 were observed in individuals with
hyperhomocysteinemia. Note that these nutrients are
interrelated in the metabolic cycle of homocysteine
4,8,9
.
67
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
Individuals with hyper-homocysteinememia also
presented lower serum folate and vitamin B6 and B12
concentrations according to the results obtained by
Refsum et al.
24
The low availability of folate in the body,
indicated by low serum or erythrocyte concentrations
suggests that the remethylation pathway of homocysteine
to methionine may be dependent on betaine as a donor
of the methyl group, which reinforces the importance of
adequate intake of betaine and choline for the reduction
of homocysteine in individuals from São Paulo.
In this study, individuals in the lowest stratum of per
capita household income had a prevalence of
hyperhomocysteinemia greater than individuals in the
highest income strata. According to the literature
25,26
, the
socioeconomic factor is important and consistent
predictor of morbidity and mortality. However, there are
no studies in the literature that investigate the inuence
of socioeconomic variables in plasma homocysteine
concentration in individuals, making it difficult to
compare and interpret the results.
Plasma concentrations of homocysteine showed a
downward trend from the rst to the last tertile of intake of
betaine for many of the categories studied. Although it is
not possible to establish causality due to the cross-sectional
design, this study suggests that consumption of betaine
exercises a protective role against the increase of plasma
homocysteine in individuals from the city of São Paulo.
The foods that most contributed to the inclusion of
betaine in the diet include breads, cereals and pasta, foods
that are also sources of other nutrients involved in
homocysteine metabolism, such as the B complex
vitamins.
Higher choline consumption was associated with lower
plasma homocysteine levels to a smaller number of
variables, such as sex (male and female), per capita
income (higher than one minimum wage) and alcoholism
(alcohol consumers). Thus, the results point to the
protective role of choline on plasma homocysteine in
specic subgroups of the population. It should be noted
that the foods that most contribute for choline intake
were animal foods (beef, poultry and eggs), which are
also sources of protein, which can increase the endogenous
production of homocysteine. Thus, the protective effect
of choline can be counterbalanced by the proteins of
animal origin in the diet, resulting in no association with
plasma homocysteine, as observed in most of the
individuals studied.
In relation to smoking, there was no difference in the
prevalence of hyperhomocysteinemia. It is known that
smoking promotes increased homocysteine
27,28
concentrations and smokers tend to have lower
circulating levels of vitamins B6, B12 and folate, nutrients
that are related to the metabolism of homocysteine
28,29
.
The highest intake of betaine was associated with lower
homocysteine levels for smokers; for choline, the highest
consumption levels were associated with decreased
homocysteine only for nonsmokers. Although the reason
for these results is not clear, it is possible that differences
in food intake between the groups could explain the
effects of choline and betaine to homocysteine reduction.
With regard to alcohol consumption, there was no
difference in the prevalence of hyperhomocysteinemia
among consumers and non-consumers. However, the
effects of alcohol on homocysteine plasma concentrations
seem to vary according to the degree of consumption.
Higher total plasma homocysteine concentrations are
directly related to chronic and excessive consumption of
alcohol
30
, possibly by interference of alcohol in the cycle of
methionine
31
and the antagonistic action in the metabolism
of folate
32
. However, moderate consumption of alcohol
(≤
2 drinks/day) seems to have an effect on lowering total
homocysteine
33
. Thus, the ndings in the literature suggest
an ambiguous effect of alcohol in relation to homocysteine,
exercising a protective effect when ingested moderately;
and a harmful effect when consumed excessively
33
.
In the present study, plasma homocysteine concentrations
among alcohol users revealed a downward trend
according to tertiles of choline and betaine intake. In a
previous study, Cho et al
9
observed that even when folate
intake is low, as long as choline and betaine intakes are
adequate, metabolism of the methyl group can function
properly. It is possible that the interference of excessive
alcohol consumption in the folate metabolism reinforces
the importance of betaine and choline in the remethylation
of homocysteine.
Despite the protective role in the reduction of
homocysteine levels and thus in the reduction of
cardiovascular risk, recent studies
34,35
show that
n-trimethylamine oxide (TMAO), a metabolite formed
from the intestinal microbiota of nutrients containing
trimethylamine, such as choline, is associated with the
pathogenesis of atherosclerosis and the severity of
cardiovascular diseases.
The limitations of this study are worth mentioning. Since
the data were obtained from a cross-sectional study, one
should be cautious in assuming conclusions about the
causal effect of exposure of interest on the biochemical
factors studied. In addition, there is no data on genetic
variations that are known to affect plasma homocysteine
concentrations.
68
Lopes et al.
Bethaine and Coline Related to Plasma Homocysteine
Int J Cardiovasc Sci. 2015; 1(1):61-69
Original Manuscript
Conclusions
This study suggests the importance of food sources of
betaine for their protective role in relation to high plasma
levels of homocysteine in individuals from the city of São
Paulo. As for choline, the results indicate a protective
effect in specic subgroups of the population, considering
that animal proteins can counteract its effect, resulting
in the lack of association with plasma homocysteine.
Potential Conflicts of Interest
No relevant conicts of interest.
Sources of Funding
This study received financial support from the Conselho
Nacional de Desenvolvimento Cientíco e Tecnológico CNPq
(proceedings no. 473100/2009-6 and no. 124652/2010-7) and
Fundação de Amparo à Pesquisa do Estado de São Paulo -
FAPESP (proceeding no. 2009/15831-0).
Academic Association
This study is not associated to any graduate programs.
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Objective —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. Design —Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. Setting —Population-based cohort in Framingham, Mass. Participants —A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. Main Outcome Measures —Plasma homocysteine concentration correlated with plasma folate, vitamin B12, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. Results —Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Conclusions —These results indicate a strong association between homocysteine concentration and folate, vitamin B12, and vitamin B6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status.(JAMA. 1993;270:2693-2698)
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Objective Few studies have examined the roles of homocysteine and related nutrients in the development of peripheral artery disease (PAD). We examined the associations between plasma homocysteine, dietary B vitamins, betaine, choline, and supplemental folic acid use and incidence of PAD. Methods We used two cohort studies of 72,348 women in the Nurses' Health Study (NHS, 1990–2010) and 44,504 men in the Health Professionals Follow-up Study (HPFS, 1986–2010). We measured plasma homocysteine in nested matched case–control studies of clinically recognized PAD within both cohorts, including 143 PAD cases and 424 controls within the NHS (1990–2010) and 143 PAD cases and 428 controls within the HPFS (1994–2008). We examined the association between diet and risk of incident PAD in the cohorts using a food frequency questionnaire and 790 cases of PAD over 3.1 million person-years of follow-up. Results Higher homocysteine levels were positively associated with risk of PAD in men (adjusted IRR 2.17; 95% CI, 1.08–4.38 for tertile 3 vs. 1). There was no evidence of an association in women (adjusted IRR 1.14; 95% CI, 0.61–2.12). Similarly, higher folate intake, including supplements, was inversely associated with risk of PAD in men (adjusted HR 0.90; 95% CI, 0.82–0.98 for each 250 μg increase) but not women (HR 1.01, 95% CI, 0.88–1.15). Intakes of the other B vitamins, betaine, and choline were not consistently associated with risk of PAD in men or women. Conclusion Homocysteine levels were positively associated and dietary folate intake was inversely associated with risk of PAD in men but not in women.