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European Journal of Clinical Nutrition (2022 )Cite this article

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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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 https://www.ukbiobank.ac.uk/.

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.

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

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

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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.

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.

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.

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

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

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.

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.

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

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.

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.

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.

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

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(www.ukbiobank.ac.uk/).

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).

These authors contributed equally: Boya Zhang, Haoyu Dong.

School of Public Health, Medical College of Soochow University, Suzhou, China

Boya Zhang, Haoyu Dong, Ying Xu, Duo Xu & Hongpeng Sun

Department of Global Health, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China

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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.

Correspondence to Hongpeng Sun or Liyuan Han.

The authors declare no competing interests.

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). https://doi.org/10.1038/s41430-022-01206-2

DOI: https://doi.org/10.1038/s41430-022-01206-2

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European Journal of Clinical Nutrition (Eur J Clin Nutr) ISSN 1476-5640 (online) ISSN 0954-3007 (print)