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

Wageningen University, Wageningen, The Netherlands.
European Journal of Clinical Nutrition (Impact Factor: 2.71). 04/2008; 62(3):386-94. DOI: 10.1038/sj.ejcn.1602725
Source: PubMed


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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Available from: Margreet Olthof, Jul 30, 2014
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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. "
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    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.
    Full-text · Article · Jun 2010 · Clinical biochemistry
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    • "Because inflammation plays a role in atherogenesis, high intake of choline and betaine may protect against cardiovascular disease. However, two recent large prospective studies, based on the participants in the Dutch PROSPECT–EPIC cohort (Dalmeijer et al. 2007) and in the Atherosclerosis Risk in Communities (ARIC) study (Bidulescu et al. 2007), respectively, demonstrated no association between intake of choline and betaine and cardiovascular disease. Whether these null findings are related to the large measurement error of intake estimates for micronutrients such choline and betaine (Bidulescu et al. 2009) should be addressed in future studies. "
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    ABSTRACT: Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine-homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B₂, B₆, and B₁₂) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.
    Full-text · Article · May 2010 · Journal of Inherited Metabolic Disease
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    • "Accurate analysis of choline intake was previously not possible because the choline content of most foods was not known until recently [1,2]. During the past five years, several major population studies reported on the associations between high dietary intakes of choline and betaine and pathological conditions or markers of disease such as plasma total homocysteine (an inverse association in the Framingham Heart Study [11] and in the Nurses' Health Study [12]), incident coronary heart disease (marginally positive association in the Atherosclerosis Risk in Communities Study [30] and in the European Prospective Investigation into Cancer and Nutrition [31]), colorectal adenoma (positive association in the Nurses' Health Study [32]) and neural tube defects in offspring (negative association in a case-control study in California [10]). In a study that assessed the variability of dietary intake of choline in human subjects [33] in a clinical research setting, when healthy male and female volunteers were asked to select ad libitum a variety of foods, the standard deviations of choline in the total measured diet were 157 mg/day for males and 88 mg/day for females corresponding to a mean dietary intake of 631 mg/day for men, respectively 443 mg/day for women. "
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    ABSTRACT: The repeatability of a risk factor measurement affects the ability to accurately ascertain its association with a specific outcome. Choline is involved in methylation of homocysteine, a putative risk factor for cardiovascular disease, to methionine through a betaine-dependent pathway (one-carbon metabolism). It is unknown whether dietary intake of choline meets the recommended Adequate Intake (AI) proposed for choline (550 mg/day for men and 425 mg/day for women). The Estimated Average Requirement (EAR) remains to be established in population settings. Our objectives were to ascertain the reliability of choline and related nutrients (folate and methionine) intakes assessed with a brief food frequency questionnaire (FFQ) and to estimate dietary intake of choline and betaine in a bi-ethnic population. We estimated the FFQ dietary instrument reliability for the Atherosclerosis Risk in Communities (ARIC) study and the measurement error for choline and related nutrients from a stratified random sample of the ARIC study participants at the second visit, 1990-92 (N = 1,004). In ARIC, a population-based cohort of 15,792 men and women aged 45-64 years (1987-89) recruited at four locales in the U.S., diet was assessed in 15,706 baseline study participants using a version of the Willett 61-item FFQ, expanded to include some ethnic foods. Intraindividual variability for choline, folate and methionine were estimated using mixed models regression. Measurement error was substantial for the nutrients considered. The reliability coefficients were 0.50 for choline (0.50 for choline plus betaine), 0.53 for folate, 0.48 for methionine and 0.43 for total energy intake. In the ARIC population, the median and the 75th percentile of dietary choline intake were 284 mg/day and 367 mg/day, respectively. 94% of men and 89% of women had an intake of choline below that proposed as AI. African Americans had a lower dietary intake of choline in both genders. The three-year reliability of reported dietary intake was similar for choline and related nutrients, in the range as that published in the literature for other micronutrients. Using a brief FFQ to estimate intake, the majority of individuals in the ARIC cohort had an intake of choline below the values proposed as AI.
    Full-text · Article · Mar 2009 · Nutrition Journal
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