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Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study^1,2,3

¹ From the Department of Nutrition Science–Dietetics, Harokopio University, Athens, Greece (PD, DBP, and SA), and the First Cardiology Clinic, School of Medicine, University of Athens, Athens, Greece (CP and CS)

See corresponding editorial on page 277.

² Supported by research grants from the Hellenic Cardiological Society and the Hellenic Atherosclerosis Society.

³ Reprints not available. Address correspondence to DB Panagiotakos, 46 Paleon Polemiston St Glyfada, Attica 166 74, Greece. E-mail: d.b.panagiotakos{at}usa.net.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Choline and betaine are found in a variety of plant and animal foods and were recently shown to be associated with decreased homocysteine concentrations.

Objective: The scope of this work was to investigate the associations between dietary choline and betaine consumption and various markers of low-grade systemic inflammation.

Design: Under the context of a cross-sectional survey that enrolled 1514 men (18–87 y of age) and 1528 women (18–89 y of age) with no history of cardiovascular disease (the ATTICA Study), fasting blood samples were collected and inflammatory markers were measured. Dietary habits were evaluated with a validated food-frequency questionnaire, and the intakes of choline and betaine were calculated from food-composition tables.

Results: Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein (P < 0.05), 26% lower concentrations of interleukin-6 (P < 0.05), and 6% lower concentrations of tumor necrosis factor- (P < 0.01). Similarly, participants who consumed >360 mg/d of betaine had, on average, 10% lower concentrations of homocysteine (P < 0.01), 19% lower concentrations of C-reactive protein (P < 0.1), and 12% lower concentrations of tumor necrosis factor- (P < 0.05) than did those who consumed <260 mg/d. These findings were independent of various sociodemographic, lifestyle, and clinical characteristics of the participants.

Conclusions: Our results support an association between choline and betaine intakes and the inflammation process in free-eating and apparently healthy adults. However, further studies are needed to confirm or refute our findings.

Key Words: Inflammation • cardiovascular disease • risk factors • diet • choline • betaine

	INTRODUCTION

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Choline is a component found in a variety of foods of both animal (eg, liver, eggs, pork, beef, cod, shrimp, and salmon) and plant (eg, dried soybeans, oat bran, Brussels sprouts, broccoli, and cauliflower) origin (1). It can be also endogenously synthesized in the liver from phosphatidylethanolamine, a reaction catalyzed by phosphatidylethanolamine N-methyltransferase with S-adenosylmethionine acting as a methyl donor. However, humans following a diet deplete of choline can develop signs of deficiency (2). Betaine, a derivative of choline, can be found in dietary sources such as wheat germ, spinach, shrimp, wheat bread, and raw mushrooms (1). Although choline was discovered almost 150 y ago, it was not until 1998 that the Institute of Medicine listed it as an essential nutrient and emphasized the need to further study the "effects of choline intake to health parameters" (3). This quaternary amine serves as a structural constituent of membrane phospholipids, such as phosphatidylcholine, choline plasmalogens, and sphingomyelin (3). Other biological actions of choline include cholinergic neurotransmission, platelet-activating-factor formation, hepatic secretion of VLDLs, and methyl transport (3). Indeed, choline can act as a methyl donor through its intermediate oxidation to betaine, which can subsequently convert homocysteine to methionine. Alternatively, methionine synthase methylates homocysteine by using folate (3). Apart from remethylation, homocysteine can also follow the transsulfuration pathway, which leads to its conversion to cystathionine in a reaction catalyzed by cystathionine β-synthase with vitamin B-6 as a cofactor (3). Betaine functions as an osmolyte and as a methyl donor in many pathways, including the methylation of homocysteine (4).

Low-grade inflammation is generally recognized as a central step in the pathogenesis of atherosclerosis (5). Moreover, established inflammatory biomarkers, such as C-reactive protein, interleukin-6, and tumor necrosis factor- (6), have been connected to the risk of cardiovascular events (7-9) with some exceptions (10). Homocysteine, a risk factor for cardiovascular disease (11) has also been shown to be related to inflammation (11) and atherosclerosis by being involved in endothelial dysfunction, lipoprotein oxidation, platelet activation, collagen synthesis (12), and cytokine regulation (13).

The close relation between inflammation and atherosclerosis implies that measures designed to reduce the inflammatory response could be beneficial. There is some evidence that B vitamins involved in methyl transport are linked to the inflammation state (14, 15). Given that choline has been found to blunt cytokine concentrations in animal models (16) and is involved in methyl transport through its oxidation to betaine (3), it would be interesting to test whether choline and betaine intake from the diet are related to inflammation.

To our knowledge there is no epidemiologic study connecting dietary intake of choline and betaine with inflammatory indexes. Therefore, the aim of the present work was to investigate the associations between dietary choline and betaine consumption and C-reactive protein, interleukin-6, tumor necrosis factor-, and homocysteine in apparently healthy individuals from the ATTICA study (17).

	SUBJECTS AND METHODS

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Subjects
The ATTICA epidemiologic study (17) has been carried out in the province of Attica (including 78% urban and 22% rural areas). From May 2001 to December 2002, 4056 free-living inhabitants from the Attica area with no history of cardiovascular or any other atherosclerotic disease, no chronic viral infections, no cold or flu, no acute respiratory infection, no dental problems, and no history of surgery in the past week were randomly selected to enroll in the study; 3042 agreed to participate (75% participation rate). All participants were interviewed by trained personnel (cardiologists, general practitioners, dietitians, and nurses) who used a standard questionnaire.

Power analysis showed that the number of enrolled participants is adequate to evaluate 2-sided standardized differences between tertiles of choline and betaine intakes and the investigated inflammatory indexes >0.5, achieving a statistical power >0.90 at a 5% probability level (P value). The study was approved by the Medical Research Ethics Committee of the supervised Institution and was carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association.

Dietary assessment
The dietary intake was assessed in all participants with a validated semiquantitative food-frequency questionnaire (ie, the EPIC-Greek) with attached pictures representing different portion sizes (18). The daily choline and betaine intakes were calculated by a registered dietitian for each food item based on the grams of food consumed per day multiplied by the choline or betaine content per gram of the same food. For composite traditional Greek dishes, widely accepted published recipes were considered (19) and then the total choline or betaine content of each dish was calculated as the sum of choline or betaine content of its ingredients. The values for the choline and betaine contents of foods were based on those provided by the US Department of Agriculture (1).

Sociodemographic and lifestyle variables
We recorded the mean annual income during the past 3 y and the educational level of the participants in years of school (as proxies of socioeconomic status). Current smokers were defined as those who smoked at least one cigarette per day. Occasional smokers (<7 cigarettes smoked/wk) were recorded and combined with current smokers because of their small sample size. The International Physical Activity Questionnaire was used to ascertain physical activity status (20)—an index of weekly energy expenditure based on frequency (times/wk), duration (min/time), and intensity of sports-related physical activity. Participants who reported no physical activities were defined as sedentary, whereas the rest were considered physically active. Height and weight were recorded, and body mass index (BMI) was calculated (weight in kg/height in m²).

Clinical and biochemical characteristics
Resting arterial blood pressure was measured 3 times in the right arm at the end of the physical examination while the subjects were in sitting position. Fasting blood samples were collected between 0800 and 1000. The biochemical evaluation was carried out in the same laboratory, which followed the criteria of the World Health Organization Reference Laboratories. C-reactive protein was assayed in all participants by particle-enhanced immunonephelometry (N Latex; Dade Behring Marburg GmbH, Marburg, Germany) with a range from 0.175 to 1100 mg/L. Interleukin-6 was measured in all participants with a high-sensitivity enzyme-linked immunosorbent assay (ELISA; R & D Systems Europe Ltd, Abingdon, United Kingdom) with a range from 0.156 to 10 pg/mL. The intraassay and interassay CVs were <5% for C-reactive protein and <10% for interleukin-6. Homocysteine was measured in 2200 participants according to the pulsar fluorescence method (Abbott Axsym; Diamond Diagnostics, Holliston, MA), and the CV was 5% (21). We used the ELISA method for the quantitative determination of human tumor necrosis factor- in duplicate in serum samples of 2540 participants by Quantikine HS/human tumor necrosis factor- immunoassay kit (R & D Systems Inc, Minneapolis, MN), and the CV was 7%. Serum total cholesterol was measured in all participants according to the chromatographic enzymatic method in a Technicon automatic analyzer (RA-1000; Dade Behring Marburg GmbH). The intra- and interassay CVs of cholesterol concentrations did not exceed 3%. Patients whose average blood pressure levels were 140/90 mm Hg or who were taking antihypertensive medication were classified as being hypertensive. Hypercholesterolemia was defined as a total serum cholesterol concentration >200 mg/dL or the use of lipid-lowering agents. Diabetes mellitus was defined as a fasting blood glucose >125 mg/dL or the use of antidiabetic medication.

Statistical analysis
Continuous variables are presented as means ± SDs, whereas categorical variables are presented as relative frequencies (%). Comparisons between inflammation variables and tertiles of betaine or choline intake were performed by analysis of variance (ANOVA), whereas differences in categorical variables between nutrients' tertiles were performed by using the Z test. However, because of multiple comparisons we used the Bonferroni correction to account for the increase in type I error. Finally, generalized univariate regression models were applied to test the association of inflammatory markers by choline and betaine intake group. Because of their skewed distributions, C-reactive protein and homocysteine values were log transformed. All reported P values are based on 2-sided tests and compared with a significance level of 5%. SPSS 14 (SPSS Inc, Chicago, IL) software was used for all the statistical calculations.

	RESULTS

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Mean daily choline intake was 291 ± 79 mg in men and 285 ± 75 mg in women (P = 0.26), whereas the range of intake varied from 72 to 852 mg in men and from 126 to 740 mg in women. The major sources of choline and betaine as well as the intake of these foods by the ATTICA Study participants are shown in Table 1.

Table 2

Table 3

Table 4

Table 5

	DISCUSSION

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Dietary intakes of choline and betaine
There are few epidemiologic studies concerning the relation between dietary choline or betaine intake and health variables (25-27), given that food databases for these compounds were not available until recently (1). Choline in foods can be free or bound as esters such as phosphocholine, glycerophosphocholine, sphingomyelin, and phosphatidylcholine (28). We assessed the total choline intake because discrepancies may exist when calculating the choline content of whole dishes based on the values of individual food items. It has been found that cooking does not change the total choline content of foods, but it can affect choline fractions (free choline is increased and phosphatidylcholine is decreased with cooking) (28). In this context we considered the total choline intake to be more accurate than individual choline forms. Mean choline intake was similar to the results of others who also used a food-frequency questionnaire (25-27, 29), lower compared with the results of an observation study (30), and below the adequate intake set by the Institute of Medicine (3). The estimated betaine intake in our study was higher than that recently published in other studies (25-27, 29). A possible explanation for this difference is that the food-frequency questionnaire we used included 4 separate questions for spinach and traditional spinach containing Greek dishes (spinach, spinach with rice, spinach pie, and "leafy vegetables" pie) (18); given the high betaine concentration of spinach (28), higher values may have been found. No comparison with dietary recommendations could be made because no dietary reference intake has been set for betaine.

We found in the unadjusted analysis that a greater proportion of subjects in the highest tertile than in the lowest tertile of choline intake were hypercholesterolemic. The opposite trend was observed for subjects with a high betaine intake. Dalmeijer et al (26) found that subjects with a higher betaine intake had a lower HDL-cholesterol concentration and subjects with a higher choline intake had a higher HDL-cholesterol concentration, whereas results from intervention studies have shown that high doses of both betaine and choline intake can adversely affect blood lipids (31, 32).

Inflammation markers in relation to choline and betaine intakes
The relation between low-grade inflammation and diet is still evolving. Supplementation of healthy subjects with B vitamins, which are involved in homocysteine metabolism, can lower concentrations of inflammatory molecules (15, 33), with some exceptions (34). Paradoxically, secondary intervention trials with B vitamin have shown homocysteine lowering, but seem rather unsuccessful in attenuating inflammatory indexes (35, 36)—a result that may be attributed to the presence of irreversible atheromatous lesions in the high-risk participants or to the difficulty in achieving additive benefits if patients are already under pharmacologic treatment. Choline (37) and betaine supplements have been found to decrease homocysteine concentrations (38, 39), and betaine is widely used for the treatment of homocystinuria (4). Higher dietary intake of choline (25, 26) and betaine (25) have recently been connected to lower homocysteine concentrations, whereas such an association was not confirmed for choline in our study.

As far as dietary choline is concerned, it is noteworthy that any possible effects on the measured biochemical markers are more difficult to isolate because they may be differentiated by the intake of choline subfractions (25) and masked by complex interrelations between phospholipids (28). Moreover, the endogenous synthesis of the phosphatidylcholine molecule via phosphatidylethanolamine can lead to the production of homocysteine molecules (40) and, thus, may alter any possible diet-related changes in homocysteine.

The facts that the dietary intake of choline showed no association with homocysteine, that the interrelation of homocysteine and C-reactive protein was not confirmed in intervention trials (35, 36, 41), and that the investigated dietary components have additional actions in animal studies (eg, prevent macrophage activation, reduce nuclear factor -B) (16) suggest that homocysteine may not be the only mechanism through which dietary betaine and choline are associated with inflammation.

In this context, it can be hypothesized that both dietary choline (42) and betaine (43) can attenuate inflammatory response by increasing S-adenosylmethionine (SAM) and reducing S-adenosylhomocysteine (SAH), the ratio of which regulates the activities of most methyltransferases. An elevation of SAM can prevent the induction of inducible nitric oxide synthase (44), attenuate the production of nuclear factor -B (45), and increase the production of glutathione (46), which in turn is involved in cytokine regulation (47). Moreover, SAM activates cystathionine β-synthase, which irreversibly converts homocysteine to cystathionine in selected tissues (48). Cystathionine can be further metabolized to cysteine and glutathione (48). A decrease in SAH would also be favorable given that it can be converted to homocysteine (43). Furthermore, products of both betaine (49) and choline (47) metabolism (eg, serine and glycine) can be used in glutathione synthesis, whereas only choline has also been proposed to be involved in intracellular signaling (16), which is related to inflammatory response.

Whatever mechanism underlies our findings, it is important that the magnitude of the observed differences concerning the concentrations of inflammatory indexes between the subjects in the highest compared with the lowest tertile of dietary choline or betaine intake is similar to those observed in subjects following the Mediterranean diet (50) or consuming high amounts of n–3 fatty acids (51). Using our results as a starting point, one can hypothesize that a higher intake of choline and betaine from the diet might be protective against inflammation and related diseases. However, it is worth referring to 2 recent large-scale studies—the Prospect–EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, which showed no relation of choline or betaine intake with cardiovascular disease risk (26), and the Atherosclerosis Risk in Communities (ARIC) study, which found no relation between dietary choline or choline plus betaine and incident coronary heart disease (27). A factor masking a possible relation of choline or betaine with the examined endpoints may be the relatively low range of choline and betaine intakes, as the authors suggest (26). Moreover, in the EPIC cohort, only 4.4% of the recruited subjects had a diagnosis of cardiovascular disease (26), a relatively low proportion that may have attenuated any possible correlation between dietary intake of the examined dietary components and cardiovascular disease.

Some limitations of our study have to be considered along with the interpretation of our results. The ATTICA study was cross-sectional; therefore, it could not establish causal relations but could only generate a hypothesis. Thus, to prove causality, randomized trials must be carried out. The misreporting of various food items consumed can be a potential confounder. Another limitation is that we calculated choline and betaine intakes through international, not national, food-composition tables. This may reflect the calculation of the amount of actual choline and betaine intakes concentrated in the foods usually consumed in Greece. Thus, to moderate the potential bias, we used tertiles of choline and betaine intakes, instead of quantitative variables.

In conclusion, the present study was the first to show a relation between inflammation and dietary intake of choline and betaine in a free-eating, population-based sample of cardiovascular disease–free adults. In particular, we found that a greater intake of these compounds from the diet was independently associated with a reduction in inflammation indexes that are believed to have an important role in cardiovascular disease. Nevertheless, because of the cross-sectional design of the present study, further randomized clinical trials are needed to confirm or refute our finding.

	ACKNOWLEDGMENTS

 
We thank the participants of the ATTICA study; the field investigators (Yannis Skoumas, Christina Chrysohoou, Natassa Katinioti, Akis Zeimbekis, Spiros Vellas, Efi Tsetsekou, Constantina Massoura, Ioanna Papaioannou, and Labros Papadimitriou) for the physical examinations; Manolis Economou, Marina Toutouza, Constadina Tselika, and Sia Poulopoulou for the biochemical evaluation; Carmen Vassiliadou and George Dedoussis for the genetic analysis; Manolis Kambaxis and Konstadina Palliou for the nutritional evaluation; and Maria Toutouza for the database management.

The authors' responsibilities were as follows—PD: wrote the manuscript; DBP: designed the study, performed the analysis, and interpreted the results; SA: drafted the manuscript; CP: designed the study and critically reviewed the manuscript; and CS: critically reviewed the manuscript. None of the authors had any conflict of interest.

	REFERENCES

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1. Howe JC, Williams JR, Holden JM. USDA database for the choline content of common foods—2004. Version current 4 May 2004. Internet: http://www.nal.usda.gov/fnic/foodcomp/data/choline/choline.html (accessed 8 November 2007).
2. Zeisel SH, Da Costa KA, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J 1991; 5:2093–8.[Abstract]
3. Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B 6, folate, vitamin B 12, pantothenic acid, biotin, and choline. Washington, DC: The National Academies Press, 1998.
4. Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004; 80:539–49.[Abstract/Free Full Text]
5. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–26.[Free Full Text]
6. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003; 108:2317–22.[Abstract/Free Full Text]
7. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999; 281:1817–21.[Abstract/Free Full Text]
8. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–11.[Abstract/Free Full Text]
9. Refsum H, Nurk E, Smith AD, et al. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr 2006; 136(suppl):1731S–40S.[Abstract/Free Full Text]
10. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997; 17:1947–53.[Abstract/Free Full Text]
11. Shai I, Stampfer MJ, Ma J, et al. Homocysteine as a risk factor for coronary heart diseases and its association with inflammatory biomarkers, lipids and dietary factors. Atherosclerosis 2004; 177:375–81.[Medline]
12. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338:1042–50.[Free Full Text]
13. Su SJ, Huang LW, Pai LS, Liu HW, Chang KL. Homocysteine at pathophysiologic concentrations activates human monocyte and induces cytokine expression and inhibits macrophage migration inhibitory factor expression. Nutrition 2005; 21:994–1002.[Medline]
14. Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 2001; 103:2788–91.[Abstract/Free Full Text]
15. Ullegaddi R, Powers HJ, Gariballa SE. B-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke. Clin Sci (Lond) 2004; 107:477–84.[Medline]
16. Rivera CA, Wheeler MD, Enomoto N, Thurman RG. A choline-rich diet improves survival in a rat model of endotoxin shock. Am J Physiol 1998; 275:G862–7.[Medline]
17. Panagiotakos DB, Pitsavos CH, Chrysohoou C, et al. Status and management of hypertension in Greece: role of the adoption of a Mediterranean diet: the Attica study. J Hypertens 2003; 21:1483–9.[Medline]
18. Katsouyanni K, Rimm EB, Gnardellis C, Trichopoulos D, Polychronopoulos E, Trichopoulou A. Reproducibility and relative validity of an extensive semi-quantitative food frequency questionnaire using dietary records and biochemical markers among Greek schoolteachers. Int J Epidemiol 1997; 26(suppl):S118–27.[Abstract/Free Full Text]
19. Trichopoulou A. Composition tables of foods and Greek dishes. Athens, Greece: Scientific Publications Parisianou SA, 2004.
20. Hallal PC, Victora CG. Reliability and validity of the International Physical Activity Questionnaire (IPAQ). Med Sci Sports Exerc 2004; 36:556.
21. Fiskerstrand T, Refsum H, Kvalheim G, Ueland P. Homocysteine and another thiols in plasma and urine: automated determination and sample stability. Clin Chem 1993; 39:263–71.[Abstract]
22. Wener M, Daum P, McQuillan G. The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration. J Rheumatol 2000; 27:2351–9.[Medline]
23. Bermudez EA, Rifai N, Buring J, Manson JE, Ridker PM. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler Thromb Vasc Biol 2002; 22:1668–73.[Abstract/Free Full Text]
24. Ward M, McNulty H, Pentieva K, et al. Fluctuations in dietary methionine intake do not alter plasma homocysteine concentration in healthy men. J Nutr 2000; 130:2653–7.[Abstract/Free Full Text]
25. Cho E, Zeisel SH, Jacques P, et al. Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr 2006; 83:905–11.[Abstract/Free Full Text]
26. Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT. Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur J Clin Nutr (Epub ahead of print 21 March 2007).
27. Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc Disord 2007;7:20.[Medline]
28. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr 2003;133:1302–7.[Abstract/Free Full Text]
29. Shaw G, Carmichael S, Yang W, Selvin S, Schaffer D. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol 2004;160:102–9.[Abstract/Free Full Text]
30. Fischer LM, Scearce JA, Mar MH, et al. Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. J Nutr 2005;135:826–9.[Abstract/Free Full Text]
31. Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med 2005;2:135.
32. Schwab U, Torronen A, Toppinen L, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr 2002;76:961–7.[Abstract/Free Full Text]
33. Solini A, Santini E, Ferrannini E. Effect of short-term folic acid supplementation on insulin sensitivity and inflammatory markers in overweight subjects. Int J Obes (Lond) 2006;30:1197–202.[Medline]
34. Peeters AC, van Aken BE, Blom HJ, Reitsma PH, den Heijer M. The effect of homocysteine reduction by B-vitamin supplementation on inflammatory markers. Clin Chem Lab Med 2007;45:54–8.[Medline]
35. Bleie O, Semb AG, Grundt H, et al. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. J Intern Med 2007;262:244–53.[Medline]
36. Schernthaner GH, Plank C, Minar E, Bieglmayer C, Koppensteiner R, Schernthaner G. No effect of homocysteine-lowering therapy on vascular inflammation and haemostasis in peripheral arterial occlusive disease. Eur J Clin Invest 2006;36:333–9.[Medline]
37. Olthof M, Brink E, Katan M, Verhoef P. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 2005;82:111–7.[Abstract/Free Full Text]
38. Olthof MR, Verhoef P. Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Curr Drug Metab 2005;6:15–22.[Medline]
39. Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr 2003;133:1291–5.[Abstract/Free Full Text]
40. Jacobs R, Stead L, Devlin C, et al. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice. J Biol Chem 2005;280:28299–305.[Abstract/Free Full Text]
41. Jonasson T, Ohlin AK, Gottsater A, Hultberg B, Ohlin H. Plasma homocysteine and markers for oxidative stress and inflammation in patients with coronary artery disease–a prospective randomized study of vitamin supplementation. Clin Chem Lab Med 2005;43:628–34.[Medline]
42. Innis S, Davidson F, Melynk S, James S. Choline-related supplements improve abnormal plasma methionine-homocysteine metabolites and glutathione status in children with cystic fibrosis. Am J Clin Nutr 2007;85:702–8.[Abstract/Free Full Text]
43. Purohit V, Abdelmalek M, Barve S, et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 2007;86:14–24.[Abstract/Free Full Text]
44. Majano PL, Garcia-Monzon C, Garcia-Trevijano ER, et al. S-Adenosylmethionine modulates inducible nitric oxide synthase gene expression in rat liver and isolated hepatocytes. J Hepatol 2001;35:692–9.[Medline]
45. Chawla RK, Watson WH, Eastin CE, Lee EY, Schmidt J, McClain CJ. S-Adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am J Physiol 1998;275:G125–9.[Medline]
46. Song Z, Zhou Z, Chen T, et al. S-Adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice. J Nutr Biochem 2003;14:591–7.[Medline]
47. Grimble RF. The effects of sulfur amino acid intake on immune function in humans. J Nutr 2006;136(suppl):1660S–5S.[Abstract/Free Full Text]
48. Brosnan J, Brosnan M. The sulfur-containing amino acids: an overview. J Nutr 2006;136(suppl):1636S–40S.[Abstract/Free Full Text]
49. Kim SK, Kim SY, Kim YC. Effect of betaine administration on metabolism of hepatic glutathione in rats. Arch Pharm Res 1998;21:790–2.[Medline]
50. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol 2004;44:152–8.[Abstract/Free Full Text]
51. Lopez-Garcia E, Schulze MB, Manson JE, et al. Consumption of (n–3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr 2004;134:1806–11.[Abstract/Free Full Text]

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				M. Yannakoulia, N. Yiannakouris, L. Melistas, E. Fappa, N. Vidra, M. D Kontogianni, and C. S Mantzoros Dietary factors associated with plasma high molecular weight and total adiponectin levels in apparently healthy women Eur. J. Endocrinol., October 1, 2008; 159(4): R5 - R10. [Abstract] [Full Text] [PDF]

				S. Slow, J. Elmslie, and M. Lever Dietary betaine and inflammation Am. J. Clinical Nutrition, July 1, 2008; 88(1): 247 - 248. [Full Text] [PDF]

				P. Detopoulou, D. Panagiotakos, S. Antonopoulou, C. Pitsavos, and C. Stefanadis Reply to S Slow et al Am. J. Clinical Nutrition, July 1, 2008; 88(1): 248 - 248. [Full Text] [PDF]

				S. V. Konstantinova, G. S. Tell, S. E. Vollset, O. Nygard, O. Bleie, and P. M. Ueland Divergent Associations of Plasma Choline and Betaine with Components of Metabolic Syndrome in Middle Age and Elderly Men and Women J. Nutr., May 1, 2008; 138(5): 914 - 920. [Abstract] [Full Text] [PDF]

				S. H Zeisel Is there a new component of the Mediterranean diet that reduces inflammation? Am. J. Clinical Nutrition, February 1, 2008; 87(2): 277 - 278. [Full Text] [PDF]

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