Betaine and Folate Status as Cooperative Determinants of Plasma Homocysteine in Humans

Abstract

Objective-Two published studies have demonstrated that betaine in the circulation is a determinant of plasma total homocysteine, but none had sufficient power to investigate the possible effect modification by folate status. Methods and Results-We measured homocysteine, betaine, folate, vitamin B 6 , and related compounds in serum/plasma from 500 healthy men and women aged 34 to 69 years before (fasting levels) and 6 hours after a standard methionine loading test. Choline, dimethylglycine, and folate were determinants of plasma betaine in a multiple regression model adjusting for age and sex. The increase in homocysteine after loading showed a strong inverse association with plasma betaine and a weaker inverse association with folate and vitamin B 6 . Fasting homocysteine showed a strong inverse relation to folate, a weak relation to plasma betaine, and no relation to vitamin B 6 . Notably, adjusted (for age and sex) dose-response curves for the postmethionine increase in homocysteine or fasting homocysteine versus betaine showed that the inverse associations were most pronounced at low serum folate, an observation that was confirmed by analyses of interaction. Conclusions-Collectively, these results show that plasma betaine is a strong determinant of increase in homocysteine after methionine loading, particularly in subjects with low folate status. Key Words: betaine Ⅲ choline Ⅲ homocysteine Ⅲ folate Ⅲ methionine T he concentration of total homocysteine (tHcy) in serum/ plasma is associated with risk of occlusive cardiovascular vascular disease (CVD). 1 Most studies have investigated basal concentration of tHcy, often obtained after an overnight fasting (fasting tHcy). The high concentration of tHcy detected after a standard methionine loading dose (postmethionine load [PML] tHcy) seems to be a risk factor independent of fasting tHcy, 2 and fasting and PML tHcy identify overlapping but also different subjects with hyperhomocysteinemia and increased CVD risk. 2 The PML increase in tHcy (PML ⌬tHcy) can be calculated as the difference between PML tHcy and fasting tHcy, but its separate role in CVD risk assessment is not settled.Determinants of fasting tHcy include genetic and a variety of lifestyle factors and pathologies. 3 Strong predictors of fasting tHcy include renal function and cobalamin and folate status. 2 The methylenetetrahydrofolate reductase 677C3 T polymorphism is the most influential common genetic factor. 4 PML tHcy and ⌬tHcy have some determinants in common with fasting tHcy, including folate status and the methylenetetrahydrofolate reductase 677C3 T polymorphism, whereas renal function seems to have minor impact. Vitamin B 6 status has been reported to have a moderate effect on PML tHcy and a weaker or essentially no effect on fasting tHcy, 2 which is in agreement with the role of the vitamin B 6 -dependent transsulfuration pathway in degrading superfluous homocysteine. 5 The effect of these B vitamins are explained by their role in homocysteine metabolism, as depicted in Figure 1.Betaine (trimet...

Plasma Dimethylglycine and Risk of Incident Acute Myocardial Infarction in Patients With Stable Angina Pectoris

“…15 However, in agreement with a recent meta-analysis, 20 we did not observe any overall association between the BHMT 742 G>A genotype and extent of CAD in the present study. As in previous reports 3,14,21 plasma DMG levels in the current study were higher in men than in women. DMG was also higher among patients with established CAD risk factors, such as older age, hypertension, and smoking.…”

“…8,22 B vitamins are important as cofactors in 1-carbon metabolism, and folate deficiency has been related to increased BHMT flux. 21 DMG tended to be weakly, inversely related to serum folate at baseline in nonfasting subjects, and folic acid supplementation (in WENBIT) seemed to prevent a time-dependent 4% to 10% increase in plasma DMG during follow-up. There was a positive association between baseline plasma DMG and methylmalonic acid, although no relationship was observed between DMG and cobalamin levels.…”

Hyperhomocysteinemia Induced by Guanidinoacetic Acid Is Effectively Suppressed by Choline and Betaine in Rats

“…Previous studies have shown that betaine is effective in suppressing methionine-induced hyperhomocysteinemia in humans 33,34) and rats. 35,36) In rats, Yagisawa et al 35,36) found that hyperhomocysteinemia induced by intravenous injection with methionine was suppressed by concurrent injection with betaine or dietary supplementation with betaine.…”

Divergent Associations of Plasma Choline and Betaine with Components of Metabolic Syndrome in Middle Age and Elderly Men and Women ,

“…The strong effect of gender has been explained by transcriptional regulation of human BHMT by estrogen and androgen (30), and the marked relation to folate by the function of betaine and 5-methyltetrahydrofolate as interchangeable sources of 1-carbon units (8,31).…”