Dietary choline and betaine; associations with subclinical markers of cardiovascular disease risk and incidence of CVD, coronary heart disease and stroke: the Jackson Heart Study



Several mechanisms have been described through which dietary intake of choline and its derivative betaine may be associated in both directions with subclinical atherosclerosis. We assessed the association of dietary intake of choline and betaine with cardiovascular risk and markers of subclinical cardiovascular disease.


Data from 3924 Jackson Heart Study (JHS) African-American participants with complete food frequency questionnaire at baseline and follow-up measurements of heart disease measures were used. Multivariable linear regression models were employed to assess associations between choline and betaine intake with carotid intima-media thickness, coronary artery calcium, abdominal aortic calcium and left ventricular mass. Cox proportional hazards regression models were used to estimate associations with time to incident coronary heart disease (CHD), ischemic stroke and cardiovascular disease (CVD).


During an average nine years of follow-up, 124 incident CHD events, 75 incident stroke events and 153 incident CVD events were documented. In women, greater choline intake was associated with lower left ventricular mass (p = 0.0006 for trend across choline quartiles) and with abdominal aortic calcium score. Among all JHS participants, there was a statistically significant inverse association between dietary choline intake and incident stroke, β = −0.33 (p = 0.04). Betaine intake was associated with greater risk of incident CHD when comparing the third quartile of intake with the lowest quartile of intake (HR 1.89, 95 % CI 1.14, 3.15).


Among our African-American participants, higher dietary choline intake was associated with a lower risk of incident ischemic stroke, and thus putative dietary benefits. Higher dietary betaine intake was associated with a nonlinear higher risk of incident CHD.

This is a preview of subscription content, access via your institution.


  1. 1.

    Niculescu MD, Zeisel SH (2002) Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 132(8 Suppl):2333S–2335S

    CAS  Article  Google Scholar 

  2. 2.

    Zeisel SH (2008) Is there a new component of the Mediterranean diet that reduces inflammation? Am J Clin Nutr 87(2):277–278

    CAS  Article  Google Scholar 

  3. 3.

    Dong C, Yoon W, Goldschmidt-Clermont PJ (2002) DNA methylation and atherosclerosis. J Nutr 132(8 Suppl):2406S–2409S

    CAS  Article  Google Scholar 

  4. 4.

    Zaina S, Lindholm MW, Lund G (2005) Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia? J Nutr 135(1):5–8

    CAS  Article  Google Scholar 

  5. 5.

    da Costa KA, Gaffney CE, Fischer LM, Zeisel SH (2005) Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr 81(2):440–444

    Article  Google Scholar 

  6. 6.

    Homocysteine Studies C (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. J Am Med Assoc 288(16):2015–2022

    Article  Google Scholar 

  7. 7.

    Wu LL, Wu JT (2002) Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta 322(1–2):21–28

    CAS  Article  Google Scholar 

  8. 8.

    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346(7):476–483

    CAS  Article  Google Scholar 

  9. 9.

    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, de Groot LC, Hofman A, Witteman JC, van Leeuwen JP et al (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350(20):2033–2041

    Article  Google Scholar 

  10. 10.

    Zeisel SH (2000) Choline: an essential nutrient for humans. Nutrition 16(7–8):669–671

    CAS  Article  Google Scholar 

  11. 11.

    Shaw GM, Finnell RH, Blom HJ, Carmichael SL, Vollset SE, Yang W, Ueland PM (2009) Choline and risk of neural tube defects in a folate-fortified population. Epidemiology 20(5):714–719

    Article  Google Scholar 

  12. 12.

    Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng TY et al (2014) Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res 74(24):7442–7452

    CAS  Article  Google Scholar 

  13. 13.

    Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT (2008) Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur J Clin Nutr 62(3):386–394

    CAS  Article  Google Scholar 

  14. 14.

    Zeisel SH (2013) Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis. Clin Chem Lab Med 51(3):467–475

    CAS  Article  Google Scholar 

  15. 15.

    Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C (2008) Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr 87(2):424–430

    CAS  Article  Google Scholar 

  16. 16.

    Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G (2007) Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc Disord 7:20

    Article  Google Scholar 

  17. 17.

    Taylor HA Jr (2005) The Jackson Heart Study: an overview. Ethn Dis 15(4 Suppl 6):S6-1–S6-3

    Google Scholar 

  18. 18.

    Taylor HA Jr, Wilson JG, Jones DW, Sarpong DF, Srinivasan A, Garrison RJ, Nelson C, Wyatt SB (2005) Toward resolution of cardiovascular health disparities in African Americans: design and methods of the Jackson Heart Study. Ethn Dis 15(4 Suppl 6):S6-4–S6-17

    Google Scholar 

  19. 19.

    Carithers T, Dubbert PM, Crook E, Davy B, Wyatt SB, Bogle ML, Taylor HA Jr, Tucker KL (2005) Dietary assessment in African Americans: methods used in the Jackson Heart Study. Ethn Dis 15(4 Suppl 6):S6-49–S6-55

    Google Scholar 

  20. 20.

    Zeisel SH, Mar MH, Howe JC, Holden JM (2003) Concentrations of choline-containing compounds and betaine in common foods. J Nutr 133(5):1302–1307

    CAS  Google Scholar 

  21. 21.

    Newell A (2006) USDA launches searchable database of foods. AWHONN Lifelines 10(2):167–169

    Article  Google Scholar 

  22. 22.

    Miller PE, Mitchell DC, Harala PL, Pettit JM, Smiciklas-Wright H, Hartman TJ (2011) Development and evaluation of a method for calculating the Healthy Eating Index-2005 using the nutrition data system for research. Public Health Nutr 14(2):306–313

    Article  Google Scholar 

  23. 23.

    Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G (2009) Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study. Nutr J 8:14

    Article  Google Scholar 

  24. 24.

    Keku E, Rosamond W, Taylor HA Jr, Garrison R, Wyatt SB, Richard M, Jenkins B, Reeves L, Sarpong D (2005) Cardiovascular disease event classification in the Jackson Heart Study: methods and procedures. Ethn Dis 15(4 Suppl 6):S6-62–S6-70

    Google Scholar 

  25. 25.

    Taylor HA Jr (2003) Establishing a foundation for cardiovascular disease research in an African-American community: the Jackson Heart Study. Ethn Dis 13(4):411–413

    Google Scholar 

  26. 26.

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612

    Article  Google Scholar 

  27. 27.

    Foppa M, Duncan BB, Rohde LE (2005) Echocardiography-based left ventricular mass estimation: how should we define hypertrophy? Cardiovasc Ultrasound 3(1):1–13

    Article  Google Scholar 

  28. 28.

    Gatto NM, Henderson VW, St John JA, McCleary C, Detrano R, Hodis HN, Mack WJ (2009) Subclinical atherosclerosis is weakly associated with lower cognitive function in healthy hyperhomocysteinemic adults without clinical cardiovascular disease. Int J Geriatr Psychiatry 24(4):390–399

    Article  Google Scholar 

  29. 29.

    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15(4):827–832

    CAS  Article  Google Scholar 

  30. 30.

    Fernandez-Sola J (2015) Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol 12(10):576–587

    Article  Google Scholar 

  31. 31.

    Marshall TA (2011) Dietary guidelines for Americans, 2010: an update. J Am Dent Assoc 142(6):654–656

    Article  Google Scholar 

  32. 32.

    Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57(6):450–458

    CAS  Article  Google Scholar 

  33. 33.

    Haring B, Wang W, Lee ET, Jhamnani S, Howard BV, Devereux RB (2015) Effect of dietary sodium and potassium intake on left ventricular diastolic function and mass in adults</=40 years (from the Strong Heart Study). Am J Cardiol 115(9):1244–1248

    CAS  Article  Google Scholar 

  34. 34.

    Institute SAS: SAS/STAT user’s guide, version 8. 1999

  35. 35.

    Institute of Medicine, Food and Nutrition Board (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. The National Academies Press, Washington. doi:10.17226/6015

  36. 36.

    Craig SA (2004) Betaine in human nutrition. Am J Clin Nutr 80(3):539–549

    CAS  Article  Google Scholar 

  37. 37.

    Milani RV, Lavie CJ (2008) Homocysteine: the Rubik’s cube of cardiovascular risk factors. Mayo Clin Proc 83(11):1200–1202

    Article  Google Scholar 

  38. 38.

    Medina M, Urdiales JL, Amores-Sanchez MI (2001) Roles of homocysteine in cell metabolism: old and new functions. Eur J Biochem/FEBS 268(14):3871–3882

    CAS  Article  Google Scholar 

  39. 39.

    Finkelstein JD, Harris BJ, Kyle WE (1972) Methionine metabolism in mammals: kinetic study of betaine-homocysteine methyltransferase. Arch Biochem Biophys 153(1):320–324

    CAS  Article  Google Scholar 

  40. 40.

    Steenge GR, Verhoef P, Katan MB (2003) Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr 133(5):1291–1295

    CAS  Google Scholar 

  41. 41.

    Cho E, Zeisel SH, Jacques P, Selhub J, Dougherty L, Colditz GA, Willett WC (2006) 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 83(4):905–911

    CAS  Article  Google Scholar 

  42. 42.

    Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, Nakagawa Y, Takahashi A, Suzuki H, Sone H et al (2004) SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat Cell Biol 6(4):351–357

    CAS  Article  Google Scholar 

  43. 43.

    Purohit V, Abdelmalek MF, Barve S, Benevenga NJ, Halsted CH, Kaplowitz N, Kharbanda KK, Liu Q-Y, Lu SC, McClain CJ et al (2007) Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 86(1):14–24

    CAS  Article  Google Scholar 

  44. 44.

    Muraoka T, Aoki K, Iwasaki T, Shinoda K, Nakamura A, Aburatani H, Mori S, Tokuyama K, Kubota N, Kadowaki T et al (2011) Ezetimibe decreases SREBP-1c expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet. Metab, Clin Exp 60(5):617–628

    CAS  Article  Google Scholar 

  45. 45.

    Bertoia ML, Pai JK, Cooke JP, Joosten MM, Mittleman MA, Rimm EB, Mukamal KJ (2014) Plasma homocysteine, dietary B vitamins, betaine, and choline and risk of peripheral artery disease. Atherosclerosis 235(1):94–101

    CAS  Article  Google Scholar 

  46. 46.

    Cho E, Holmes MD, Hankinson SE, Willett WC (2010) Choline and betaine intake and risk of breast cancer among post-menopausal women. Br J Cancer 102(3):489–494

    CAS  Article  Google Scholar 

  47. 47.

    Cho E, Willett WC, Colditz GA, Fuchs CS, Wu K, Chan AT, Zeisel SH, Giovannucci EL (2007) Dietary choline and betaine and the risk of distal colorectal adenoma in women. J Natl Cancer Inst 99(16):1224–1231

    Article  Google Scholar 

  48. 48.

    Kotsopoulos J, Hankinson SE, Tworoger SS (2010) Dietary betaine and choline intake are not associated with risk of epithelial ovarian cancer. Eur J Clin Nutr 64(1):111–114

    CAS  Article  Google Scholar 

  49. 49.

    Lee JE, Giovannucci E, Fuchs CS, Willett WC, Zeisel SH, Cho E (2010) Choline and betaine intake and the risk of colorectal cancer in men. Cancer Epidemiol, Biomark Prev 19(3):884–887

    CAS  Article  Google Scholar 

  50. 50.

    Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341):57–63

    CAS  Article  Google Scholar 

Download references


The JHS is supported and conducted in collaboration with Jackson State University (N01-HC-95170), University of Mississippi Medical Center (N01-HC-95171), and Tougaloo College (N01-HC-95172) NIH contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Center on Minority Health and Health Disparities (NCMHD) with additional support from NHLBI contract HL076784 and the National Institute of Aging (AG028321). The investigators thank JHS study participants and staff for their valuable contributions and acknowledge the important contributions of Janice Maras, at Northeastern University, to the calculation of the choline and betaine variables. The results described in this article have been presented in part during the American Heart Association Scientific Sessions Conference, November 2014 in Chicago, IL, USA. AB and KLT designed research; HRM, SKM and AB conducted research; HRM, SKM, DTD and AB analyzed data; AB, DTD and KLT wrote the paper; and AB had primary responsibility for final content. All authors read and approved the final manuscript.

Author information



Corresponding author

Correspondence to Aurelian Bidulescu.

Ethics declarations

Conflict of interest

None of the authors had a personal or financial conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Millard, H.R., Musani, S.K., Dibaba, D.T. et al. Dietary choline and betaine; associations with subclinical markers of cardiovascular disease risk and incidence of CVD, coronary heart disease and stroke: the Jackson Heart Study. Eur J Nutr 57, 51–60 (2018).

Download citation


  • Diet
  • Choline
  • Betaine
  • Subclinical measures of cardiovascular disease
  • Incident coronary heart disease
  • The Jackson Heart Study