Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women

ArticleinEuropean Journal of Clinical Nutrition 62(3):386-94 · April 2008with27 Reads
Impact Factor: 2.71 · DOI: 10.1038/sj.ejcn.1602725 · Source: PubMed
Abstract

To investigate the association between dietary intakes of folate, betaine and choline and the risk of cardiovascular disease (CVD). Prospective cohort study. Subjects: A total of 16 165 women aged 49-70 years without prior CVD. Subjects were breast cancer screening participants in the PROSPECT-EPIC cohort, which is 1 of the 2 Dutch contributions to the European Prospective Investigation into Cancer and Nutrition (EPIC). Each participant completed a validated food frequency questionnaire. Folate intake was calculated with the Dutch National Food Database. Betaine and choline intakes were calculated with the USDA database containing choline and betaine contents of common US foods. Data on coronary heart disease (CHD) events and cerebrovascular accident (CVA) events morbidity data were obtained from the Dutch Centre for Health Care Information. During a median follow-up period of 97 months, 717 women were diagnosed with CVD. After adjustment, neither folate, nor betaine, nor choline intakes were associated with CVD (hazard ratios for highest versus lowest quartile were 1.23 (95% confidence interval 0.75; 2.01), 0.90 (0.69; 1.17), 1.04 (0.71; 1.53), respectively). In a subsample of the population, high folate and choline intakes were statistically significantly associated with lower homocysteine levels. High betaine intake was associated with slightly lower high-density lipoprotein (HDL)-cholesterol concentrations. Regular dietary intakes of folate, betaine and choline were not associated with CVD risk in post-menopausal Dutch women. However, the effect of doses of betaine and choline beyond regular dietary intake--for example, via supplementation or fortification--remains unknown.

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ORIGINAL ARTICLE
Prospective study on dietary intakes of folate,
betaine, and choline and cardiovascular disease risk
in women
GW Dalmeijer
1,3
, MR Olthof
1,2
, P Verhoef
1,2
, ML Bots
3
and YT van der Schouw
3
1
Wageningen University, Wageningen, The Netherlands;
2
Wageningen Centre for Food Sciences, Wageningen, The Netherlands and
3
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
Objective: To investigate the association between dietary intakes of folate, betaine and choline and the risk of cardiovascular
disease (CVD).
Design: Prospective cohort study.
Subjects: A total of 16 165 women aged 49–70 years without prior CVD. Subjects were breast cancer screening participants in
the PROSPECT–EPIC cohort, which is 1 of the 2 Dutch contributions to the European Prospective Investigation into Cancer and
Nutrition (EPIC).
Methods: Each participant completed a validated food frequency questionnaire. Folate intake was calculated with the Dutch
National Food Database. Betaine and choline intakes were calculated with the USDA database containing choline and betaine
contents of common US foods. Data on coronary heart disease (CHD) events and cerebrovascular accident (CVA) events
morbidity data were obtained from the Dutch Centre for Health Care Information.
Results: During a median follow-up period of 97 months, 717 women were diagnosed with CVD. After adjustment, neither
folate, nor betaine, nor choline intakes were associated with CVD (hazard ratios for highest versus lowest quartile were 1.23
(95% confidence interval 0.75; 2.01), 0.90 (0.69; 1.17), 1.04 (0.71; 1.53), respectively). In a subsample of the population, high
folate and choline intakes were statistically significantly associated with lower homocysteine levels. High betaine intake was
associated with slightly lower high-density lipoprotein (HDL)-cholesterol concentrations.
Conclusion: Regular dietary intakes of folate, betaine and choline were not associated with CVD risk in post-menopausal Dutch
women. However, the effect of doses of betaine and choline beyond regular dietary intake – for example, via supplementation
or fortification remains unknown.
European Journal of Clinical Nutrition (2008) 62, 386394; doi:10.1038/sj.ejcn.1602725; published online 21 March 2007
Keywords: betaine; choline; folate; homocysteine; cholesterol; cardiovascular disease
Introduction
A high plasma homocysteine concentration is associated
with increased risk of cardiovascular disease (CVD) (Anon-
ymous, 2002; Klerk et al., 2002), but causality of the
association is not yet proven. Some clinical trials of
homocysteine lowering through B-vitamin treatment sup-
port this hypothesis (Schnyder et al., 2001, 2002), but other
more recent ones do not (Baker et al., 2002; Lange et al.,
2004; Toole et al., 2004; Bonaa et al., 2006; HOPE 2
Investigators, 2006).
Homocysteine is a breakdown product of methionine, and
can be further degraded to cysteine via vitamin B
6
-depen-
dent reactions. Alternatively, it can be remethylated into
methionine, which requires a methyl group obtained from 5-
methyltetrahydrofolate or from betaine (Figure 1) (Selhub,
1999. Supplementation with folic acid lowers plasma homo-
cysteine by about 25% maximally (van Oort et al., 2003).
Intervention studies in healthy volunteers suggest that also
Received 4 December 2005; revised 17 August 2006; accepted 13 February
2007; published online 21 March 2007
Correspondence: Dr YT van der Schouw, University Medical Center Utrecht,
Julius Center for Health Sciences and Primary Care, STR 6.131, PO Box 85500,
3508 GA Utrecht, The Netherlands.
E-mail: y.t.vanderschouw@umcutrecht.nl
Contributors: GWD carried out the data analyses and wrote the manuscript.
MRO, PV and YtvdS assisted and provided advice during all the stages of the
work. All authors contributed in the discussion and interpretation of the
results, and in drafting and editing the manuscript. No conflicts of interest are
declared.
European Journal of Clinical Nutrition (2008) 62, 386394
&
2008 Nature Publishing Group All rights reserved 0954-3007/08 $
30.00
www.nature.com/ejcn
Page 1
supplementation with high doses of betaine (1.5–6 g/day), or
its precursor choline (2.6 g/day, supplemented as phospha-
tidylcholine, the form in which choline occurs in foods)
lowers fasting concentrations of plasma homocysteine
(Schwab et al., 2002; Olthof et al., 2003, 2005a; Steenge
et al., 2003).
Unlike folate, betaine and choline supplementation also
lower plasma concentrations of homocysteine after a
methionine load (Olthof et al., 2003, 2005a; Steenge et al.,
2003). Both fasting homocysteine and the decrease of
homocysteine concentrations after a methionine loading
test predict the risk of CVD (Graham et al., 1997; Verhoef
et al., 1999). Consequently, betaine and choline may have
additional value for prevention of CVD relative to folic acid,
which lowers only fasting homocysteine. On the other hand,
studies in humans have shown that betaine supplementa-
tion above 1.5 g/day increases low-density lipoprotein
(LDL)-cholesterol and triacylglycerol concentrations and phos-
phatidylcholine supplementation increases triacylglycerol
concentrations (McGregor et al., 2002; Schwab et al., 2002;
Olthof et al., 2005b). These effects of high doses of betaine
and choline might counterbalance the potential beneficial
effects of their homocysteine-lowering properties. However,
the regular dietary intakes of betaine and choline are far
lower than the doses used in intervention studies.
Intake of betaine from foods is estimated to be 200–
400 mg/day (Shaw et al., 2004; Fischer et al., 2005). Main
food sources of betaine are wheat bran, wheat germ, spinach,
pretzels, shrimps and wheat bread (Zeisel et al., 2003).
Choline is present in the human diet primarily as lecithin,
which is the trivial name for phosphatidylcholine. Intake of
choline moieties from foods is estimated at 400–600 mg/day
(Shaw et al., 2004; Fischer et al., 2005). Main food sources of
choline are beef liver, chicken liver, eggs, wheat germ, bacon,
dried soybeans and pork (Zeisel et al., 2003).
Low folate intake is generally associated with an increased
risk of CVD (Rimm et al., 1998; Voutilainen et al., 2001;
Bazzano et al., 2002), and for stroke (Bazzano et al., 2002; He
et al., 2004). The relationship between regular dietary intake
of betaine and choline and the risk of CVD has not been
investigated yet. Therefore we investigated the association
between dietary intakes of folate, betaine and choline and
the risk of CVD in 16 165 Dutch postmenopausal women of
the Dutch PROSPECT–EPIC cohort (European Prospective
study Into Cancer and nutrition), who were followed for 8.1
years. In addition, we investigated the associations between
dietary intakes of folate, betaine and choline and plasma
homocysteine concentrations and cholesterol concentra-
tions in a subsample of 1,610 women (homocysteine in a
subsample of 903 women).
Methods
Between 1993 and 1997, 17 357 women between 49 and 70
years were recruited among breast cancer screening partici-
pants in the PROSPECT–EPIC cohort, which is 1 of the 2
Dutch contributions to the European Prospective Investiga-
tion into Cancer and Nutrition (EPIC) (Boker et al., 2001).
Of the 17 357 women, 355 women who did not consent to
linkage with vital status registries were excluded. Addition-
ally, we excluded 117 women because of missing question-
naires, 92 women because they reported an energy intake of
o500 or 46000 kcal/day and 628 women who reported a
history of CVD before the baseline measurements, leaving
16 165 women available for analysis.
Baseline measurement
At baseline a general questionnaire containing questions on
demographic characteristics, presence of chronic diseases,
and risk factors for chronic diseases, such as hypertension,
reproductive history, family history, smoking habits, drink-
ing of alcohol and physical activity was administered.
Systolic and diastolic blood pressures were measured in
duplicate at the left arm with the subjects in sitting position
after 10 min of rest with an automated and calibrated
oscillomat (Bosch & Son, Jungingen, Germany). Subse-
quently, the mean systolic and diastolic blood pressure was
calculated. Body height was measured to the nearest 0.5 cm
with a wall mounted stadiometer (Lameris, Utrecht, The
Netherlands). Body weight was measured in light indoor
clothing without shoes to the nearest 0.5 kg with a floor scale
(Seca, Atlanta, GA, USA). Body mass index (BMI) was
calculated as weight divided by height squared (kg/m
2
). We
used a questionnaire for assessment of physical activity. This
questionnaire has been validated in free living, apparently
healthy people, aged 63–80 years (Voorrips et al., 1991).
Classifications based on questionnaire activity scores showed
Spearman’s correlations of 0.78–0.73 with classifications
obtained by repeated 24-h activity recalls and pedometer
measurements, showing that the questionnaire provides a
reliable and valid method for assessing physical activity in
METHIONINE
HOMOCYSTEINE
DIMETHYL
GLYCINE
BETAINE
CHOLINE
CYSTEINE
FOLATE
Serine
Glycine
5,10-methylene
tetrahydrofolate
5-methyltetra
hydrofolate
tetrahydrofolate
methionine synthase
vitamin B-12
betaine methyl
transferase
S-adenosyl methionine
S-adenosyl homocysteine
cystathionine synthase
vitamin B-6
MTHFR
Figure 1 Schematic representation of homocysteine metabolism.
MTHFR ¼ 5,10-methylenetetrahydrofolate reductase.
Intakes of folate, betaine and choline and CVD risk
GW Dalmeijer et al
387
European Journal of Clinical Nutrition
Page 2
this age-group. Also a blood sample was taken and stored
under liquid nitrogen at 1961C.
Food frequency questionnaire (FFQ)
At the baseline visit of the PROSPECT study, each participant
completes a FFQ. The FFQ was designed and carefully
validated to estimate the intake of 178 food items in the
year preceding enrollment (Ocke et al., 1997a, b). We used
this FFQ to estimate the dietary intakes of folate, betaine and
choline. The questionnaire contained colour photographs of
2–4 different-sized portions of 21 food items, which helped
assessing the serving size. Subjects indicated their consump-
tion frequency of each food item on a daily/weekly/
monthly/yearly scale or as never consumed. For several food
items, additional questions regarding consumption fre-
quency of sub-items were asked. Questionnaires also in-
cluded some blank-spaced questions, in which names of
brands used could be filled in.
Calculation of dietary betaine, choline and folate intakes
The choline and betaine contents in individual foods were
estimated from the available data of the USDA database with
the choline and betaine contents of common US foods
(Howe et al., 2004). For the choline contents, different types
of choline are measured in the USDA-database that is, free
choline, glycerophosphocholine, phosphocholine, phospha-
tidylcholine and sphingomyelin. For this study we used the
sum of all choline moieties to estimate choline intake.
We assigned betaine and choline contents to each food
item in the food questionnaire of the PROSPECT study as
follows. For food items of our questionnaire that occurred in
the database of the USDA, we used the betaine and choline
content data available. This was possible for fruit, vegetables
and some meat products. For items in the questionnaire that
did not have a direct correspondence to a food in the USDA
database we estimated the choline and betaine contents of
nutritionally comparable foods that were available. For
example, for ‘sunflower oil’ choline and betaine values from
‘olive oil’ were assigned. Assignment of betaine and choline
values to mixed dishes in our food frequency database,
without a comparable mixed dish on the USDA database, was
based on the proportional contribution of individual food
components in the recipe. The recipe of the NEVO table
(Dutch food composition table) (NEVO, 2001) was used. If
there was no description of a recipe in the NEVO table then
the recipe of a standard Dutch recipe book was used to
decide on the individual components and their contribution
to the mixed dish (Henderson et al., 1994). We computed
women’s average daily intakes of betaine and choline by
calculating portion size and frequency of consumption of
each food item. The folate intakes of the women in this
study population were calculated by means of the Dutch
National Food Database (NEVO, 2001).
Morbidity and mortality follow-up
Data on coronary heart disease (CHD) events and cerebro-
vascular accident (CVA) events morbidity data were obtained
from the Dutch Centre for Health Care Information, which
holds a standardized computerized register of hospital
discharge diagnoses. All diagnoses were coded according to
the International Classification of diseases, Ninth Revision,
Clinical Modification (ICD-9). Follow-up was complete until
1January 2004. The database was linked to the cohort on the
basis of birth date, gender, postal code and general practi-
tioner with a validated probabilistic method (Herings et al.,
1992).
Information on vital status was obtained through linkage
with the municipal administration registries. Causes of death
were obtained from the women’s general practitioners.
For our analysis, CHD (ICD-9; 410–414,427.5) and CVA
(ICD-9; 430–438), whichever came first, were the endpoints
of interest. During the follow-up of 8.1 year in total, 717
women were diagnosed for first time with CVD; 493 with
CHD and 224 with CVA.
Biochemical analysis
Between August and October 2000, serum and plasma
samples of a randomly selected subsample of 1610 women
in the cohort were retrieved from the liquid nitrogen. Serum
total cholesterol was determined using an automated
enzymatic procedure on a Vitros 250 (Johnson & Johnson,
Rochester, NY, USA). Serum LDL- and high-density lipopro-
tein (HDL)-cholesterol were measured using a colorimetic
assy on a Hitachi 904 (Johnson & Johnson, Rochester, NY,
USA). All remaining samples were stored at 801C. In
November 2004, we selected a subsample of 903 women
who has been fasting for at least approximately 2 h before
blood sampling out of the first subsample of 1610 women. In
the blood samples of these women, the total homocysteine
concentrations (sum of all oxidized and reduced forms of
homocysteine) were measured in plasma samples with the
use of an high-performance liquid chromatography method
with fluorescence detection (Ubbink et al., 1991). Within–
and between run CVs were 3.1 and 5.9% respectively.
Data Analysis
Mean intakes and s.d. of folate, betaine and choline were
calculated. To control for total energy intake, all nutrients
were adjusted for total energy intake by using the regression
residual method (Willett and Stampfer, 1986).
We counted for each participant the person-years of
follow-up from the date of return of the questionnaire to
the date of CVD diagnosis; or the end of follow-up at 1
January 2004. Cox-regression analysis was used to quantify
the association of betaine, choline and folate intakes with
total CVD and with the subtype CHD and CVA. Folate,
betaine and choline intakes were categorized in quartiles,
and hazard ratios were calculated for quartiles with the
Intakes of folate, betaine and choline and CVD risk
GW Dalmeijer et al
388
European Journal of Clinical Nutrition
Page 3
lowest quartile of intake as the reference category. To study
the relationship between folate, betaine and choline intakes
and the risk on CVD we applied three models, that is an
unadjusted model, a basic model that adjusted for conven-
tional risk factors, and a fully adjusted model that took into
account both conventional risk factors and nutritional
factors. Linear regression analysis was used to assess the
association of folate, betaine and choline intakes with
plasma homocysteine, serum total cholesterol, LDL-choles-
terol and HDL-cholesterol. For this, folate, betaine and
choline intakes were categorized into quartiles, and differ-
ences in mean plasma homocysteine and serum cholesterol
concentrations were calculated for the three upper quartiles
of intake as compared to the lowest quartile of intake.
All analyses were conducted using SPSS for windows,
Version 12.0.1.
Results
Baseline characteristics of the study population are shown in
Table 1. Mean (7s.d.) betaine intake was 214774 mg/day,
mean choline intake was 300751 mg/day and mean folate
intake was 195740 mg/day. In total 717 women were
diagnosed with first time CVD; 493 women were diagnosed
with CHD and 224 women with CVA during follow-up
(Table 2).
In the unadjusted model and after adjustment for
potential confounders, neither betaine nor folate intakes
were associated with total CVD, CHD or cerebrovascular
disease (Table 3). High choline intake tended to correspond
with a higher risk of CHD, but this was only statistically
significant in the unadjusted model. Choline intake was
not associated with total CVD or cerebrovascular disease
(Table 3).
Mean (7s.d.) concentrations of homocysteine, total
cholesterol and HDL- and LDL-cholesterol were 12.07
3.6 mmol/l (n ¼ 903 plasma samples), 5.871.0, 1.670.4
and 4.070.9 mmol/l (n ¼ 1610 serum samples), respectively.
After adjustment for age, BMI and smoking, higher folate
intake was statistically significantly associated with lower
homocysteine levels (difference between fourth and first quartile
–0.7170.32 mmol/l, 95% CI 1.33; 0.08), but showed no
relationship with lipid levels (Table 4).
Higher betaine intake was statistically significantly asso-
ciated with lower HDL-cholesterol (difference between
fourth and first quartile 0.0670.03 mmol/l, 95% CI
0.11; 0.01), but there was no association with homo-
cysteine concentrations (Table 4). Higher choline intake was
statistically associated with lower homocysteine levels
(difference between fourth and first quartile
0.8770.35 mmol/l, 95% CI 1.56; 0.19). Further the LDL-
cholesterol concentration was higher among the second
quartile of choline intake than the first (difference
0.1470.07 mmol/l, 95% CI 0.01; 0.27), but the third and
fourth quartiles were not different from the first quartile.
Discussion
We did not find an association between regular intake of
betaine, choline or folate and CVD risk after adjustment for
potential confounders in postmenopausal women. In a
subsample of this population, we found that high choline
and folate intakes, but not betaine intake, were associated
with modestly lower homocysteine levels. Furthermore, we
found that a high betaine intake was associated with slightly
lower HDL cholesterol.
Before we interpret these findings, we will address
internal validity of the study. First, the prospective design
of our study. We assessed the average intake of dietary
betaine, choline and folate before diagnosis of CVD, which
Table 1 Baseline characteristics of the study population of 16 165
women
Variable
Mean7s.d.
Follow-up time, (months) 97719.3
Age, (years) 5776
BMI, (kg/ m
2
)2674
Systolic blood pressure, (mm Hg) 133720
Diastolic blood pressure, (mm Hg) 79710
Physicial activity 6.975.0
N (%)
Smoking status
Smoking never 7046 (43.6)
Smoking past 5582 (34.5)
Smoking current o10 1648 (10.2)
Smoking current 11-20 1337 (8.3)
Smoking current 420 548 (3.4)
Hypertension 3082 (19.1)
Diabetes 434 (2.7)
Hypercholesterolaemia 788 (4.9)
Multi vitamin status
Multivitamin, never 11753 (72.7)
Multivitamin, user 1146 (7.1)
Multivitamin, unknown 3266 (20.2)
Daily dietary intake
a
Mean7s.d.
Betaine, (mg/day) 241774
Choline, (mg/day) 300751
Folic acid, (mg/day) 195740
Energy, (kcal/day) 17987436
Protein, (% of energy) 16.172.41
Carbohydrates, (% of energy) 44.776.4
Total fat, (% of energy) 35.675.5
Saturated fat, (g/day) 2975
Monounsaturated fat, (g/day) 2675
Polyunsaturated fat, (g/day) 1374
Cholesterol, (mg/day) 199754
Dietary fibre, (g/day) 2274
Alcohol, (% of energy) 3.674.9
Vitamin B
2
, (mg/day) 1.670.4
Vitamin B
6
, (mg/day) 1.570.2
Vitamin B
12
,(mg/day) 4.371.8
Abbreviations: BMI, body mass index.
a
All dietary variables were adjusted for energy intake, except energy.
Intakes of folate, betaine and choline and CVD risk
GW Dalmeijer et al
389
European Journal of Clinical Nutrition
Page 4
eliminates the recall bias that so often hampers interpreta-
tion of findings of case–control studies, as patients might
recall their dietary habits differently than healthy controls.
Second, the estimations of dietary intakes. The questionnaire
was not validated to estimate dietary betaine, choline and
folate intakes, but has been shown to adequately assess
intake of energy, macronutrients, dietary fibre and retinol
and included several specific foods that are rich in betaine,
choline or folate (Ocke et al., 1997b). The relative validity for
bread, which contains high amounts of betaine and folate,
was good (Spearman’s correlation coefficient 0.78), whereas
for eggs, an important source of choline, the (Spearman’s
correlation coefficient was 0.43). For the most important
sources of folate, that is milk and milk products, relative
validity was good, and for vegetables it was adequate
(Spearman’s correlation coefficients 0.79, 0.31 respectively).
Although the FFQ was not validated for B vitamins, the
spearman correlations of the nutrients retinol, b-carotene,
vitamin C and vitamin D are between 0.61 and 0.81. These
correlation coefficients are all statistically significantly
different from zero. Furthermore, the validity for the major
food sources of B vitamins was also good, so we have no
reason to assume that it would be different for B vitamins
(Ocke et al., 1997a). Furthermore, our estimates of daily
betaine, choline and folate intakes were well in line with
other studies in western population (Melse-Boonstra et al.,
2002; Shaw et al., 2004; Brink et al., 2005; Fischer et al., 2005;
Larsson et al., 2005; Slow et al., 2005; Cho et al., 2006).
Therefore we feel confident that the estimated intakes of
betaine, choline and folate in our study are reliable. Never-
theless, the fact that our questionnaire was not specifically
designed for measuring intakes of folate, betaine or choline
may have led to an attenuation of the association between
these nutritional compounds and risk of CVD.
The current evidence regarding folate intake and CVD risk
from other prospective epidemiologic studies is generally in
favour of a protective effect of folate on CVD. Most
prospective studies found an inverse association between
folate intake and risk of CVD (Rimm et al., 1998; Voutilainen
et al., 2001; Bazzano et al., 2002), and for stroke (Bazzano
et al., 2002; He et al., 2004), whereas one study did not
(Al-Delaimy et al., 2004). This is sustained by prospective
studies on folate status and risk of CVD (reviewed in Table 3
of Voutilainen et al. (2001). It is important to realize that the
contrast in folate intake between the upper and lower
categories in most studies is much larger than in our study,
mainly owing to the fact that supplement use in our country
is negligible.
Results from clinical intervention trials studying long-term
effects of folic acid supplementation on CVD are incon-
clusive. Some clinical trials of homocysteine lowering
through B-vitamin treatment support a cardioprotective
effect (Schnyder et al., 2001, 2002), but others do not (Baker
et al., 2002; Lange et al., 2004; Toole et al., 2004; Bonaa et al.,
2006; HOPE 2 Investigators, 2006).
For betaine and choline, there are no other epidemiologic
studies to compare our findings with. Our risk analyses
suggested that a high choline intake may be associated with
Table 2 Data on intake, follow-up time and number of cardiovascular events per quartile of energy-adjusted betaine, choline and folate intake
Quartiles
12 34
Betaine
Betaine range (mg/day) p192 192o p234 234o p283 283o
Mean betaine intake (mg/day) 153 213 258 338
Average follow-up time, (months) 97 96 97 98
Total cardiovascular cases 188 172 178 179
CHD 127 116 124 126
CVA 61 56 54 53
Choline
Choline range in (mg/day) p266 266o p296 296o p329 329o
Mean choline intake (mg/day) 239 281 311 365
Average follow-up time, (months) 96 97 97 97
Total cardiovascular cases 166 158 188 205
CHD 108 101 127 157
CVA 58 58 61 48
Folate
Folate range (mg/day) p169 169o p191 191o p215 215o
Mean folate intake (mg/day) 151 180 202 246
Average follow-up time, (months) 97 98 97 97
Total cardiovascular cases 187 154 179 197
CHD 131 105 125 132
CVA 56 49 54 65
Abbreviations: CHD, coronary heart disease; CVA, cerebrovascular accident.
Intakes of folate, betaine and choline and CVD risk
GW Dalmeijer et al
390
European Journal of Clinical Nutrition
Page 5
higher risk of CHD. This may be mediated by a triacylglycerol-
raising effect, as suggested by a previous experiment
(Olthof et al., 2005b).
We did not find an association between betaine and
homocysteine concentrations, whereas intakes of choline
and folate were only weakly inversely associated with
concentrations of plasma homocysteine. This was probably
a consequence of the narrow ranges of intake. Hence, the
homocysteine differences between the upper and lower
quartiles were most likely too small to detect a difference
Table 3 Hazard ratios for total cardiovascular events, CHD events and CVA events by quartiles of energy-adjusted betaine, choline and folate intake
Hazard ratio (95% CI)
Variable of model First quartile Second quartile Third quartile Fourth quartile
Betaine
Total cardiovascular
Unadjusted 1 0.88 (0.69; 1.13) 0.94 (0.74; 1.19) 0.96 (0.76; 1.22)
Basic model
a
1 0.97 (0.76; 1.24) 0.97 (0.76; 1.24) 0.97 (0.76; 1.24)
Fully adjusted model
b
1 0.94 (0.73; 1.21) 0.94 (0.72; 1.20) 0.90 (0.69; 1.17)
CHD
Unadjusted 1 0.92 (0.71; 1.18) 0.97 (0.76; 1.24) 0.98 (0.77; 1.26)
Basic model
a
1 1.00 (0.78; 1.29) 1.02 (0.79; 1.31) 1.00 (0.78; 1.28)
Fully adjusted model
b
1 0.97 (0.75; 1.26) 0.98 (0.76; 1.28) 0.95 (0.72; 1.25)
CVA
Unadjusted 1 0.92 (0.64; 1.33) 0.88 (0.61; 1.26) 0.86 (0.59; 1.24)
Basic model
a
1 1.02 (0.71; 1.47) 0.92 (0.63; 1.33) 0.88 (0.61; 1.28)
Fully adjusted model
b
Choline 1 1.00 (0.69; 1.45) 0.90 (0.61; 1.33) 0.83 (0.55; 1.25)
Total cardiovascular
Unadjusted 1 0.79 (0.61; 1.02) 1.04 (0.82; 1.33) 1.22 (0.97; 1.55)
Basic model
a
1 0.78 (0.60; 1.01) 1.00 (0.78; 1.27) 1.08 (0.85; 1.38)
Fully adjusted model
c
1 0.78 (0.58; 1.03) 0.99 (0.73; 1.34) 1.04 (0.71; 1.53)
CHD
Unadjusted 1 0.93 (0.71; 1.21) 1.16 (0.90; 1.51) 1.44 (1.13; 1.84)
*
Basic model
a
1 0.91 (0.69; 1.20) 1.12 (0.86; 1.45) 1.26 (0.98; 1.62)
Fully adjusted model
c
1 0.93 (0.69; 1.25) 1.14 (0.83; 1.56) 1.28 (0.86; 1.91)
CVA
Unadjusted 1 0.97 (0.67; 1.40) 1.04 (0.73; 1.49) 0.82 (0.56; 1.20)
Basic model
a
1 0.98 (0.68; 1.42) 1.01 (0.70; 1.46) 0.73 (0.49; 1.08)
Fully adjusted model
c
1 0.95 (0.64; 1.43) 0.94 (0.60; 1.48) 0.61 (0.33; 1.13)
Folate
Total cardiovascular
Unadjusted 1 0.79 (0.61; 1.02) 0.95 (0.74; 1.20) 1.08 (0.85; 1.36)
Basic model
a
1 0.82 (0.63; 1.06) 0.95 (0.74; 1.21) 1.06 (0.83; 1.34)
Fully adjusted model
d
1 0.86 (0.64; 1.15) 1.05 (0.74; 1.49) 1.23 (0.75; 2.01)
CHD
Unadjusted 1 0.79 (0.61; 1.03) 0.96 (0.75; 1.22) 1.00 (0.79; 1.28)
Basic model
a
1 0.82 (0.63; 1.07) 0.96 (0.74; 1.23) 0.96 (0.75; 1.23)
Fully adjusted model
d
1 0.83 (0.61; 1.12) 0.99 (0.69; 1.43) 1.05 (0.62; 1.79)
CVA
Unadjusted 1 0.87 (0.59; 1.27) 0.97 (0.67; 1.41) 1.15 (0.81; 1.65)
Basic model
a
1 0.91 (0.62; 1.33) 0.97 (0.67; 1.43) 1.16 (0.81; 1.68
Fully adjusted model
d
1 0.99 (0.64; 1.54) 1.12 (0.66; 1.89) 1.38 (0.67; 2.81)
Abbreviations: CHD, coronary heart disease; CVA, cerebrovascular accident.
*
Po0.05
a
Adjusted for conventional risk factors, namely hypertension, cholesterolemia, mean systolic blood pressure, age, total physical activity, BMI (cat), smoking (never/
past/ current smoking 1–10, 11–20, and 204 cigarettes a day), and diabetes
b
Adjusted for conventional risk factors and energy, protein intake (energy-adjusted), saturated fats intake (energy-adjusted), monounsaturated fats, polyunsaturated
fats (energy-adjusted), alcohol intake (energy-adjusted), vitamin B
2
intake (energy-adjusted) vitamin B
6
intake (energy-adjusted) vitamin B
12
intake (energy-
adjusted), folate intake (energy-adjusted) and choline intake (energy-adjusted).
c
Adjusted for conventional risk factors and energy, protein intake (energy-adjusted), saturated fats intake (energy-adjusted), monounsaturated fats, polyunsaturated
fats (energy-adjusted), alcohol intake (energy-adjusted), vitamin B
2
intake (energy-adjusted) vitamin B
6
intake (energy-adjusted) vitamin B
12
intake (energy-
adjusted), betaine intake (energy-adjusted) and folate intake (energy-adjusted).
d
Adjusted for conventional risk factors and intake of energy, proteins (energy-adjusted), saturated fats (energy-adjusted), monounsaturated fats, polyunsaturated fats
(energy-adjusted), alcohol (energy-adjusted), vitamin B
2
(energy-adjusted) vitamin B
6
(energy-adjusted), vitamin B
12
(energy-adjusted), betaine (energy-adjusted)
and choline (energy-adjusted).
Intakes of folate, betaine and choline and CVD risk
GW Dalmeijer et al
391
European Journal of Clinical Nutrition
Page 6
in disease risk between the quartiles, if high homocysteine is
truly a cause of CVD, of course. Doses of betaine used in the
supplementation studies that were able to affect homocys-
teine levels are between 1.5 and 6.0 g/day, which is far higher
than the regular dietary intake (Schwab et al., 2002; Olthof
et al., 2003; Steenge et al., 2003). This also holds for choline
and to a lesser extent for folate acid. In addition the blood
sampling in this study was not optimized for homocysteine
analyses. Subjects were not completely fasted, blood was not
kept cool after sampling and plasma was not prepared within
an hour after sampling. All these factors may have con-
tributed to a large variation in homocysteine values, where-
by the relationships between betaine, choline and folate
intakes and homocysteine concentrations are weakened. Cho
et al. (2006) also examined the relationships between choline
and betaine and plasma homocysteine in 1960 subjects. They
found that higher intakes of dietary choline and betaine were
related to lower total homocysteine concentration. However
the range of betaine and choline intake in their study was
somewhat broader than in our study.
We did not find any significant associations between
intake of betaine, choline and folate intakes and total
cholesterol levels. Women in the fourth quartile of betaine
intake had slightly lower HDL-cholesterol levels than
women in the first quartile, but they did not have a higher
risk of CVD. Intervention studies suggest that high doses of
betaine and choline increase blood lipids (McGregor et al.,
2002; Schwab et al., 2002; Olthof et al., 2005b). However, the
dietary intakes of betaine and choline found in the current
study are far below the doses used in intervention studies.
Therefore, we conclude that intakes of betaine and choline
in the dietary range are probably not strongly related to
increased lipid concentrations. However, high intakes of
betaine or choline, for example, with supplements, may
increase lipid levels (Olthof et al., 2005b).
Conclusion
Regular dietary intakes of betaine, choline and folate were
not associated with CVD risk in postmenopausal Dutch
women. In line with this, associations of these nutritional
compounds with homocysteine and lipids were absent or
small. However, there may of course be an effect of high
doses of these compounds, that is, beyond regular dietary
intakes, on CVD risk.
Acknowledgements
The skilful help of JJMM Drijvers, dietician, and JH den
Breeijen, MSc, with calculations of betaine and choline
intakes is gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
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Page 9
    • "However, the sample in the present study was small; therefore, further investigation is needed to confirm these results. There is a strong potential for GPC supplements to improve health; for example, choline supplementation may acutely decrease the risk of cardiovascular diseases [24,25] and increase learning and memory performance [26]. These findings bolster the need for an improved understanding of the mechanism of the action of GPC in healthy subjects. "
    [Show abstract] [Hide abstract] ABSTRACT: α-Glycerophosphocholine (GPC) is a putative acetylcholine precursor that potentially increases growth hormone secretion through the action of acetylcholine-stimulated catecholamine. The aim of this study was to investigate acute physiologic responses to a single intake of GPC. Eight healthy male subjects (25 ± 1 y old) ingested GPC 1000 mg or a placebo in a double-blind randomized crossover study. Fasting blood samples were obtained before the administration of GPC (baseline) and 60 and 120 min after administration. All subjects repeated the identical protocol using the placebo. Plasma free choline levels significantly increased at 60 and 120 min after GPC administration. Plasma growth hormone secretion was increased significantly 60 min after taking GPC, whereas no significant change was observed with the placebo. In addition, the serum free fatty acid was increased 120 min after GPC ingestion, but no changes were seen with the placebo. Moreover, serum acetoacetate and 3-hydroxybutyrate levels, which are indices of hepatic fat oxidation, were increased at 120 min after taking GPC, whereas the placebo had no effect. These findings suggest that a single dose of GPC increases growth hormone secretion and hepatic fat oxidation, with concomitant increases in choline levels, in young adults.
    Full-text · Article · Jun 2012 · Nutrition
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    • "Because inflammation plays such a key role in atherogenesis, or the development of plaque build-up in arteries, the authors concluded that high intake of these nutrients may protect against CVD. However, two large prospective studies conducted in 2007 based on the subjects in the Dutch PROSPECT-EPIC cohort [70] and the Atherosclerosis Risk in Communities (ARIC) study [71] demonstrated no association between choline and betaine consumption and CVD. It has been noted, however, that these null findings may be due to the large measurement error of intake estimates for choline and betaine [72]. "
    [Show abstract] [Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most common liver condition in the developed world and may progress to more severe forms of disease such as cirrhosis or liver cancer. Thus, steps taken to reduce its prevalence through preventative nutritional approaches such as functional foods and nutraceuticals (FFN) should be pursued. It is well known that certain lipotropic nutrients such as choline and metabolites betaine and phosphatidylcholine (PC; lecithin) could prevent or alleviate fatty liver through a variety of mechanisms, including increased hepatic VLDL secretion. Animal and human studies have demonstrated clear protective effects of choline, betaine and PC for NAFLD as well as possible roles in CVD prevention from epidemiological data. Currently, choline consumption is below dietary recommendations due in large part to a general lack of understanding regarding the importance of this nutrient for human health. As lecithin is commonly added (in small amounts) in many processed foods due to its functional capabilities, it is projected that increasing its abundance in the food supply and increasing consumer education and acceptance of lecithin-based functional foods and nutraceuticals may represent a progressive step towards preventing liver and whole-body metabolic pathologies in many areas of the world.
    Full-text · Article · Apr 2012 · European Journal of Lipid Science and Technology
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    • "However, there are few studies that directly test a connection between betaine supply and vascular disease. In healthy subjects, short-or medium-term betaine supplementation does not improve flow-mediated vasodilation, a marker of endothelial function, despite reduced homocysteine [124], and prospective general population studies in Holland [125] and the United States [43] failed to detect an association between the intake of choline and betaine and cardiovascular disease. Thus, the claims made that the nutritional supplement " TMG " will protect against vascular disease have not been substantiated , though the effects of long-term use of supplemental betaine have not been tested, and it would be particularly interesting to see the results of studies on at-risk sections of the population (for example, those with the metabolic syndrome or those who are losing excessive betaine) that should benefit from an increased betaine intake. "
    [Show abstract] [Hide abstract] ABSTRACT: Betaine is an essential osmolyte and source of methyl groups and comes from either the diet or by the oxidation of choline. Its metabolism methylates homocysteine to methionine, also producing N,N-dimethylglycine. Betaine insufficiency is associated with the metabolic syndrome, lipid disorders and diabetes, and may have a role in vascular and other diseases. Betaine is important in development, from the pre-implantation embryo to infancy. Betaine supplementation improves animal and poultry health, but the effect of long-term supplementation on humans is not known, though reports that it improves athletic performance will stimulate further studies. Subsets of the population that may benefit from betaine supplementation could be identified by the laboratory, in particular those who excessively lose betaine through the urine.Plasma betaine is highly individual, in women typically 20–60 μmol/L and in men 25–75 μmol/L. Plasma dimethylglycine is typically < 10 μmol/L. Urine betaine excretion is minimal, even following a large betaine dose. It is constant, highly individual and normally < 35 mmol/mole creatinine. The preferred method of betaine measurement is by LC-MS/MS, which is rapid and capable of automation. Slower HPLC methods give comparable results. Proton NMR spectrometry is another option but caution is needed to avoid confusion with trimethylamine-N-oxide.
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