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Dietary intake of antioxidant vitamins and risk of stroke: the Japan Public Health Center–based Prospective Study

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Epidemiologic evidence on the relationship between antioxidant vitamin intake and stroke is limited. We aimed to investigate the association between dietary intake of antioxidant vitamins and the incidence of total stroke and ischemic stroke.


The subjects were 82 044 Japanese men and women aged 45–74 years under the Japan Public Health Center-based Prospective Cohort Study. Between 1995 and 1997, dietary assessment was done using a food frequency questionnaire. During 983 857 person-years of follow-up until the end of 2009 we documented 3541 incident total strokes and 2138 ischemic strokes.


Dietary intakes of α-carotene, β-carotene, α-tocopherol and vitamin C were not inversely associated with the incidence of total stroke and ischemic stroke adjustment for cardiovascular risk factors and selected lifestyle variables. When stratified by current smoking status, the inverse association between dietary vitamin C intake and incidence of total stroke observed among non-smokers but not smokers, with respective multivariable hazard ratios for the highest versus lowest quintiles of vitamin C of 0.81 (95% confidence interval (CI), 0.68–0.96; P-trend=0.03) among non-smokers; and 1.03 (0.84–1.25; P-trend=0.55) among smokers. As for ischemic stroke, the corresponding multivariable hazard ratios were 0.76 (0.60–0.96; P-trend=0.02) among non-smokers; and 1.00 (0.78–1.28; P-trend=0.61) among smokers.


Dietary vitamin C intake was inversely associated with the incidence of total stroke and ischemic stroke among non-smokers.

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  1. 1

    Tapiero H, Townsend DM, Tew KD . The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother 2004; 58: 100–110.

  2. 2

    Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF Jr, Vita JA . Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996; 93: 1107–1113.

  3. 3

    Burlakova EB, Krashakov SA, Khrapova NG . The role of tocopherols in biomembrane lipid peroxidation. Membr Cell Biol 1998; 12: 173–211.

  4. 4

    Engin KN . Alpha-tocopherol: looking beyond an antioxidant. Mol Vis 2009; 15: 855–860.

  5. 5

    Asplund K . Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. J Intern Med 2002; 251: 372–392.

  6. 6

    Del Rio D, Agnoli C, Pellegrini N, Krogh V, Brighenti F, Mazzeo T et al. Total antioxidant capacity of the diet is associated with lower risk of ischemic stroke in a large Italian cohort. J Nutr 2011; 141: 118–123.

  7. 7

    Voko Z, Hollander M, Hofman A, Koudstaal PJ, Breteler MM . Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 2003; 61: 1273–1275.

  8. 8

    Kubota Y, Iso H, Date C, Kikuchi S, Watanabe Y, Wada Y et al. Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: the Japan Collaborative Cohort Study (JACC) study. Stroke 2011; 42: 1665–1672.

  9. 9

    Ross RK, Yuan JM, Henderson BE, Park J, Gao YT, Yu MC . Prospective evaluation of dietary and other predictors of fatal stroke in Shanghai, China. Circulation 1997; 96: 50–55.

  10. 10

    Yochum LA, Folsom AR, Kushi LH . Intake of antioxidant vitamins and risk of death from stroke in postmenopausal women. Am J Clin Nutr 2000; 72: 476–483.

  11. 11

    Ascherio A, Rimm EB, Hernan MA, Giovannucci E, Kawachi I, Stampfer MJ et al. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann Intern Med 1999; 130: 963–970.

  12. 12

    Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P . Intake of flavonoids, carotenoids, vitamins C and E, and risk of stroke in male smokers. Stroke 2000; 31: 2301–2306.

  13. 13

    He FJ, Nowson CA, MacGregor GA . Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 2006; 367: 320–326.

  14. 14

    Tsugane S, Sawada N . The JPHC study: design and some findings on the typical Japanese diet. Jpn J Clin Oncol 2014; 44: 777–782.

  15. 15

    Tsubono Y, Takamori S, Kobayashi M, Takahashi T, Iwase Y, Iitoi Y et al. A data-based approach for designing a semiquantitative food frequency questionnaire for a population-based prospective study in Japan. J Epidemiol 1996; 6: 45–53.

  16. 16

    Ministry of Education, Culture, Sports, Science and Technology. Standard Tables of Food Composition in Japan. The fifth revised ed, Tokyo 2002.

  17. 17

    Ishihara J, Inoue M, Kobayashi M, Tanaka S, Yamamoto S, Iso H et al. Group JFVS. Impact of the revision of a nutrient database on the validity of a self-administered food frequency questionnaire (FFQ). J Epidemiol 2006; 16: 107–116.

  18. 18

    Sasaki S, Ishihara J, Tsugane S . Reproducibility of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I to assess food and nutrient intake. J Epidemiol 2003; 13: S115–S124.

  19. 19

    Ishihara J, Sobue T, Yamamoto S, Yoshimi I, Sasaki S, Kobayashi M et al. Validity and reproducibility of a self-administered food frequency questionnaire in the JPHC Study Cohort II: study design, participant profile and results in comparison with Cohort I. J Epidemiol 2003; 13: S134–S147.

  20. 20

    Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y et al. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation 2006; 113: 195–202.

  21. 21

    Walker AE, Robins M, Weinfeld FD . The National Survey of Stroke. Clinical findings. Stroke 1981; 12: I13–I44.

  22. 22

    Li Y, Schellhorn HE . New developments and novel therapeutic perspectives for vitamin C. J Nutr 2007; 137: 2171–2184.

  23. 23

    Ito Y, Kurata M, Suzuki K, Hamajima N, Hishida H, Aoki K . Cardiovascular disease mortality and serum carotenoid levels: a Japanese population-based follow-up study. J Epidemiol 2006; 16: 154–160.

  24. 24

    Hak AE, Ma J, Powell CB, Campos H, Gaziano JM, Willett WC et al. Prospective study of plasma carotenoids and tocopherols in relation to risk of ischemic stroke. Stroke 2004; 35: 1584–1588.

  25. 25

    Ito Y, Suzuki K, Ishii J, Hishida H, Tamakoshi A, Hamajima N et al. A population-based follow-up study on mortality from cancer or cardiovascular disease and serum carotenoids, retinol and tocopherols in Japanese inhabitants. Asian Pac J Cancer Prev 2006; 7: 533–546.

  26. 26

    Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP . Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999; 30: 2535–2540.

  27. 27

    Karppi J, Laukkanen JA, Sivenius J, Ronkainen K, Kurl S . Serum lycopene decreases the risk of stroke in men: a population-based follow-up study. Neurology 2012; 79: 1540–1547.

  28. 28

    Gey KF, Stahelin HB, Eichholzer M . Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study. Clin Investig 1993; 71: 3–6.

  29. 29

    O'Donnell CJ, Ridker PM, Glynn RJ, Berger K, Ajani U, Manson JE et al. Hypertension and borderline isolated systolic hypertension increase risks of cardiovascular disease and mortality in male physicians. Circulation 1997; 95: 1132–1137.

  30. 30

    Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996; 334: 1145–1149.

  31. 31

    The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–1035.

  32. 32

    Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005; 294: 56–65.

  33. 33

    Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ . Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003; 361: 2017–2023.

  34. 34

    Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH . Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 2004; 164: 1552–1556.

  35. 35

    Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T . Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010; 341: c5702.

  36. 36

    Gale CR, Martyn CN, Winter PD, Cooper C . Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. BMJ 1995; 310: 1563–1566.

  37. 37

    Myint PK, Luben RN, Welch AA, Bingham SA, Wareham NJ, Khaw KT . Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr 2008; 87: 64–69.

  38. 38

    Yokoyama T, Date C, Kokubo Y, Yoshiike N, Matsumura Y, Tanaka H . Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a Japanese rural community. The Shibata study. Stroke 2000; 31: 2287–2294.

  39. 39

    Myint PK, Luben RN, Wareham NJ, Bingham SA, Khaw KT . Combined effect of health behaviours and risk of first ever stroke in 20,040 men and women over 11 years' follow-up in Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): prospective population study. BMJ 2009; 338: b349.

  40. 40

    Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 2008; 300: 2123–2133.

  41. 41

    Bingham SA, Gill C, Welch A, Cassidy A, Runswick SA, Oakes S et al. Validation of dietary assessment methods in the UK arm of EPIC using weighed records, and 24-hour urinary nitrogen and potassium and serum vitamin C and carotenoids as biomarkers. Int J Epidemiol 1997; 26 (Suppl 1), S137–S151.

  42. 42

    Yang M, Wang Y, Davis CG, Lee SG, Fernandez ML, Koo SI et al. Validation of an FFQ to assess short-term antioxidant intake against 30 d food records and plasma biomarkers. Public Health Nutr 2014; 17: 297–306.

  43. 43

    Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL . Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004; 110: 637–641.

  44. 44

    Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academy Press: Washington, DC, USA, 2000.

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This study was supported by National Cancer Center Research and Development Fund (23-A-31 [toku] and 26-A-2) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). This study was supported by Grants-in-Aid for Center Research and for the 3rd Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan. We are indebted to the Aomori, Iwate, Ibaraki, Niigata, Osaka, Kochi, Nagasaki and Okinawa Cancer Registries for providing their incidence data. Members of the Japan Public Health Center-based Prospective Study (JPHC Study, principal investigator: S Tsugane) Group are shown in Supplementary Material. Funding for this study was obtained by one of the authors (ST). Support was also obtained in the form of a financial contribution from the AXA Research Fund to one of the authors (MI) as chair holder of the AXA Department of Health and Human Security, Graduate School of Medicine, The University of Tokyo. The AXA Research Fund had no role in the study design, data collection, analysis, interpretation or manuscript drafting or in the decision to submit the manuscript for publication.

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Correspondence to H Iso or S Tsugane.

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Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

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