In our study, intakes of choline and betaine predicted plasma tHcy concentrations independent of other important predictors, including intakes of folate and B vitamins. The inverse association between choline plus betaine and tHcy concentrations was manifested among participants with low folate intake and participants consuming alcohol.
Choline has several biological functions. Along with folate, it is a source of methyl groups. Choline is oxidized to betaine, which can donate a methyl group to homocysteine to form methionine. Choline is involved in lipid transport as a precursor for phospholipids such as phosphatidylcholine and sphingomyelin, which are incorporated into cellular membrane and are involved in signal transduction (1
). Choline affects nerve signaling as a precursor for the neurotransmitter acetylcholine and is essential in brain development and normal memory function (43
). Perturbation of phospholipid metabolism and neurotransmitter production may underlie development of degenerative diseases such as Alzheimer disease. Animal studies have found that prolonged depletion of choline promotes fatty liver, DNA hypomethylation, and tumor development in the liver even in the absence of any additional carcinogens (48
). Betaine is an osmolyte; protects cells, proteins, and enzymes from environmental stress (2
); and shows a beneficial effect for atherosclerosis (9
) and fatty liver (10
). Until recently, dietary choline and betaine have not been extensively investigated in epidemiologic studies because of lack of food-composition databases. Whether choline and betaine intakes would be measured accurately by using an FFQ and whether the variation of intake in the general population is physiologically important have not been examined. Our findings provide strong evidence that choline and betaine intakes measured by FFQs are valid and support the contention that variation in intake among free-living populations is physiologically meaningful.
Although choline is synthesized in the body, humans still need choline from diet. The recommended daily intake was set in 1998 at 550 mg/d for men and 425 mg/d for women (51
). Our data show that mean intake in this population is lower than the recommended daily intake. A study measured the choline content of ad libitum diets by healthy adult volunteers housed in a clinical research center and compared these with intake from 3-d food records assessed immediately before study enrollment (52
). Male and female subjects consumed 631 and 443 mg choline/d when observed, but the intakes estimated from the food records were significantly lower. This difference between observed and reported intakes was not apparent when data were normalized for energy intake, which suggests that the choline composition of the diet was reported accurately but that energy intake was underre-ported on the food records (52
Although choline is widely available in food, our data show that most choline intake in the general population comes from only a few food sources. Humans can obtain betaine either from diet or from endogenous synthesis from choline. Most betaine intake in our population also came from limited food sources.
Methylation of homocysteine by choline and betaine is confined to the liver and kidney, but methylation of homocysteine by folate exists in all body cells (53
). Methylation pathways mediated by choline and betaine and folate are interrelated; disruption of one pathway may affect the others. Studies among animals and humans support this possibility. Animals with a choline-deficient diet had lower hepatic folate concentrations (54
), and animals with folate deficiency had depletion of hepatic choline concentrations (55
). Folate supplementation raised plasma betaine concentrations in a clinical trial (56
). Depletion and subsequent repletion of folate intake affected plasma choline concentrations (57
). An inverse association between plasma betaine and tHcy concentrations was most pronounced at low serum folate concentrations (58
). Our data also show that choline and betaine intakes affect tHcy concentrations and, presumably, methyl-group metabolism, especially when folate intake is low. In other words, even if folate intake is low, methyl-group metabolism may function properly if choline and betaine intakes are adequate. This may help explain some discrepancies in the findings of previous epidemiologic studies that examined folate intake and chronic diseases (59
). In a case-control study, higher maternal periconceptional choline and betaine intakes were associated with a reduced risk of neural tube defects, a disease related to one-carbon metabolism (7
); the multivariate odds ratio for the highest compared with lowest quartile of choline intake was 0.51 (95% CI: 0.25, 1.07), independent of folate intake.
Depletion of choline intake in humans raised plasma tHcy concentrations after a methionine load (60
), and betaine supplementation reduced the elevation of plasma tHcy concentration after a methionine load (61
). Supplementation of betaine (1.5–6 g/d or higher) was used to lower tHcy concentrations among people with hyperhomocysteinemia (53
) and lowered fasting tHcy concentrations in the general population up to 20% (61
). High-dose supplementation of choline as phosphatidylcholine (2.6 g choline/d) lowered fasting as well as postmethionine-loaded concentrations of tHcy in healthy men (62
). The doses used in those studies are not easily achieved by typical diet. Our study adds further evidence that intakes of <1 g choline or betaine/d can reduce tHcy concentrations in a free-living population.
Among the choline-containing compounds, phosphatidylcholine was not related to plasma tHcy concentrations, even though it was the largest component of total choline intake. Because phosphatidylcholine and sphingomyelin are lipid soluble, whereas other choline compounds are water soluble (6
), the former are absorbed through different pathways and may have different bioavailabilities and fates. Phosphatidylcholine supplementation did lower plasma tHcy concentrations, although the dose was much higher than that normally available from diet alone (62
We found that the association between choline plus betaine intakes and tHcy concentrations was stronger among men than among women. This may be partly due to higher folate concentrations in women than in men in this population (63
). Women may also have higher de novo synthesis of choline (48
) and lower tHcy concentrations than men (27
). A preliminary analysis of choline intake and tHcy concentrations in women did not find an association (64
In conclusion, we found that intakes of choline and betaine predicted plasma tHcy concentrations, especially when folate intakes were low. Our data support the validity of intake measured by FFQs and indicate the physiologic importance of these nutrients within the range consumed by a general population. Future epidemiologic studies examining methyl-group availability and chronic diseases should account for these nutrients in addition to folate.