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Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: a large UK population-based cohort



The evidence of relationship between dietary intake of folate, vitamin B6 and vitamin B12 and cardiovascular diseases (CVD) in UK populations is limited. We aimed to analyze the association of dietary intake of folate, vitamin B6, and vitamin B12 with CVD events [stroke, myocardial infarction (MI)] and CVD mortality.


We included 115,664 participants, aged 40–70 years, with no CVD events or cancer at baseline, enrolled between 2006 and 2010 and followed up to the end of 2018. Dietary intake was measured with an online 24-h dietary assessment. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations.


After multivariate adjustment, higher dietary folate intake was inversely associated with CVDs with hazard ratios of 0.99, 0.92, and 0.88 in groups 2–4 compared with group 1 (the lowest group); inversely associated with stroke with hazard ratios of 0.94, 0.90, and 0.86 groups 2–4 compared to group 1 (lowest group); inversely associated with MI with hazard ratios of 1.01, 0.90 and 0.86 groups 2–4 compared to group 1 (lowest group); inversely associated with CVD mortality with hazard ratios of 0.95, 0.80 and 0.74 Groups 2–4 compared to group 1 (lowest group). Each tablespoon/day higher intake of raw vegetable intake, pieces/day higher intake of fresh fruit intake bowls/week higher intake of cereal intake, and g/day higher intake of dietary fiber were associated with higher intakes of folate every 0.02,0.06,0.05, and 0.08 SD, respectively. E-value analysis suggested robustness to unmeasured confounding.


Each increase in folate intakes was related to 5% lower risks of total CVD events and 10% lower risks of CVD mortality. Our findings support that strengthening dietary folate intake as a primary prevention strategy for CVD events and CVD mortality.

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Fig. 1: Association of dietary factors with folate, vitamin B6 and vitamin B12 intakes in the UK Biobank study.
Fig. 2: Associations of dietary intakes of folate with incident CVD events and CVD mortality in the UK Biobank study.
Fig. 3: Association of dietary intake of folate with CVD events stratified by sex.

Data availability

Data may be obtained from a third party and are not publicly available. We used UK Biobank data to analyse and report the findings. Data access policy can be obtained from


  1. Hansaem C, Ji-Yun H, Yun JA, Ji-Myung K, Tae-Jin S, Namsoo C, et al. Intake of antioxidants and B vitamins is inversely associated with ischemic stroke and cerebral atherosclerosis. Nutr Res Pr. 2016;10:516–23.

    Article  Google Scholar 

  2. Shekelle P. Lowering homocysteine with folic acid and B vitamins did not prevent vascular events in vascular disease. Evid Based Med. 2006;11:104.

    Article  Google Scholar 

  3. Bazzano LA, Reynolds K, Holder KN, Jiang H. Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases. Jama. 2006;296:2720–6.

    Article  CAS  Google Scholar 

  4. Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, Josse RG, Vieth R. Supplemental vitamins and minerals for cardiovascular disease prevention and treatment: JACC focus seminar. J Am Coll Cardiol. 2021;77:423–36.

    Article  CAS  Google Scholar 

  5. Bowen KJ, Sullivan VK, Kris-Etherton PM, Petersen KS. Nutrition and cardiovascular disease-an update. Curr Atheroscler Rep. 2018;20:8.

    Article  Google Scholar 

  6. He K, Merchant A, Rimm EB. Vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke. 2004;35:169–74.

    Article  CAS  Google Scholar 

  7. Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A. Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke. 2010;41:1285–9.

    Article  CAS  Google Scholar 

  8. Mcnulty H, Ward M, Hoey L, Hughes CF, Pentieva K. Addressing optimal folate and related B-vitamin status through the lifecycle: health impacts and challenges. Proc Nutr Soc. 2019;78:449–62.

    Article  Google Scholar 

  9. Guelpen BV, Hultdin J, Johansson I, Stegmayr B, Hallmans G, K Nilsson T, et al. Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective,nested case-referent study of plasma concentrations and dietary intake. Stroke. 2005;36:1426–31.

    Article  Google Scholar 

  10. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–36.

    Article  CAS  Google Scholar 

  11. Choi HS, Kim Y, Yun J, Chang NS, Kim YJ, Song T, et al. Higher antioxidant and B vitamins intake is associated with ischemic stroke and carotid atherosclerosis. Acta Oceanologica Sin. 2014;29:35–43.

    Google Scholar 

  12. Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L, et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke. 2002;33:1183–8.

    Article  CAS  Google Scholar 

  13. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age. PLoS Med. 2015;12:e1001779.

    Article  Google Scholar 

  14. Fry A, Littlejohns T, Sudlow C, Doherty N, Adamska L, Sprosen T, et al. Comparison of sociodemographic and health-related characteristics of uk biobank participants with those of the general population. Am J Epidemiol. 2017;186:1026–34.

    Article  Google Scholar 

  15. Liu B, Young H, Crowe F, Benson V, Spencer E, Key T, et al. Development and evaluation of the Oxford WebQ, a lowcost, web-based method for assessment of previous 24 h dietary intake in large-scale prospective studies. Public Health Nutr. 2011;41:1998–2005.

    Article  Google Scholar 

  16. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.

    Article  Google Scholar 

  17. Hoon LD, Nana K, Hu FB, John OE, Rimm EB, Willett WC, et al. Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study. BMJ. Clin Res. 2018;362:k2575.

    Google Scholar 

  18. Haneuse S, Vanderweele T, Arterburn D. Using the E-value to assess the potential effect of unmeasured confounding in observational studies. J Am Med Assoc. 2019;321:602–3.

    Article  Google Scholar 

  19. Walker AE, Robins M, Weinfeld FD. The national survey of stroke:clinical findings. Stroke. 1981;12:I13–I44.

    CAS  PubMed  Google Scholar 

  20. Zeitlin A, Frishman WH, Chang CJ. The association of vitamin B12 and folate blood levels with mortality and cardiovascular morbidity incidence in the old old: the Bronx Aging Study. Am J Ther. 1997;4:275–81.

    Article  CAS  Google Scholar 

  21. Hsu CY, Chiu SW, Hong KS, Saver JL, Ovbiagele B. Folic acid in stroke prevention in countries without mandatory folic acid food fortification: a meta-analysis of randomized controlled trials. J Stroke. 2018;20:99–109.

    Article  Google Scholar 

  22. Bazzano LA, Jiang H, Ogden LG, Loria CM, Suma V, Leann M, et al. Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Am J Clin Nutr. 2002;76:93–9.

    Article  CAS  Google Scholar 

  23. Clarke R, Lewington S. Homocysteine and coronary heart disease. Semin Vasc Med. 2002;02:391–400.

    Article  Google Scholar 

  24. Eikelboom, John W. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131:363–75.

    Article  CAS  Google Scholar 

  25. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, et al. Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. J Nutr. 1996;126:1258S–65S.

    Article  CAS  Google Scholar 

  26. Oksala N, Salonen T, Strandberg T, Oksala A, Erkinjuntti T. Cerebral small vessel disease and kidney function predict long-term survival in patients with acute stroke. Stroke J Cereb Circulation 2010;41:1914–20.

    Article  Google Scholar 

  27. Friso S, Lotto V, Corrocher R, Choi SW. Vitamin B6 and cardiovascular disease. Sub-Cell Biochem. 2012;56:265.

    Article  CAS  Google Scholar 

  28. Tanriverdi H, Evrengul H, Enli Y, Kuru O, Seleci D, Tanriverdi S, et al. Effect of homocysteine-induced oxidative stress on endothelial function in coronary slow-flow. Cardiology 2006;107:313–20.

    Article  Google Scholar 

  29. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N. Engl J Med. 1997;337:1631–3.

    Article  Google Scholar 

  30. Larsson SC, Mannisto S, Virtanen MJ, Kontto J, Albanes D, Virtamo J. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers. Am J Epidemiol. 2008;167:954–61.

    Article  Google Scholar 

  31. Lotto V, Choi SW, Friso S. Vitamin B6: a challenging link between nutrition and inflammation in CVD. Br J Nutr. 2011;106:183–95.

    Article  CAS  Google Scholar 

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Our research has been conducted using the UK Biobank Resource (application No 52632). Permission to use the UK Biobank Resource was approved by the access subcommittee of the UK Biobank Board(


This study is supported by the National Natural Science Foundation of China (82173648), Innovative Talent Support Plan of the Medical and Health Technology Project in Zhejiang Province (2021422878), Internal Fund of Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences (2020YJY0212), Ningbo Clinical Research Center for Digestive System Tumors (Grant No. 2019A21003), and Sanming Project of Medicine in Shenzhen (SZSM201803080).

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Authors and Affiliations



Boya Zhang performed the data analyses and wrote the manuscript; Haoyu Dong contributed significantly to manuscript preparation; Xu Ying and Xu duo contributed significantly to analysis; Hongpeng Sun and Li Yuan Han helped perform the analysis with constructive discussions. All authors reviewed the manuscript.

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Correspondence to Hongpeng Sun or Liyuan Han.

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UK Biobank has received ethics approval from the National Health Service National Research Ethics Service.

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Zhang, B., Dong, H., Xu, Y. et al. Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: a large UK population-based cohort. Eur J Clin Nutr (2022).

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