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Nutrition and Health (including climate and ecological aspects)

Fermented soy products intake and risk of cardiovascular disease and total cancer incidence: The Japan Public Health Center-based Prospective study



The association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan.


We studied 79,648 participants (42,788 women; 36,860 men) aged 45–74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995–1998) and were followed to 2009–2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products.


In women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes.


Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.

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  1. 1.

    Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet 2012;380:2095–128.

    PubMed  Google Scholar 

  2. 2.

    Joseph P, Leong D, McKee M, Anand S, Schwalm JD, Teo K, et al. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–94.

    CAS  PubMed  Google Scholar 

  3. 3.

    Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  4. 4.

    Guccione A, Felson D, Anderson J, Anthony J, Zhang Y, Wilson P, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham study. Am J Public Health. 1994;84:351–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Kattainen A, Koskinen S, Reunanen A, Martelin T, Knekt P, Aromaa A. Impact of cardiovascular diseases on activity limitations and need for help among older persons. J Clin Epidemiol. 2004;57:82–88.

    PubMed  Google Scholar 

  6. 6.

    Yabroff K, Lawrence W, Clauser S, Davis W, Brown M. Burden of illness in cancer survivors: findings from a population-based national sample. J Natl Cancer Inst. 2004;96:1322–30.

    PubMed  Google Scholar 

  7. 7.

    Oh M, Han M, Byeon Y, Bae K, Choi S. Assessing activity limitation among cancer survivors in Korea using data from a nationwide survey. Asian Pac J Cancer Prev. 2015;16:2739–43.

    PubMed  Google Scholar 

  8. 8.

    Kokubo Y, Iso H, Ishihara J, Okada K, Inoue M, Tsugane S, et al. Association of dietary intake of soy, beans, and isoflavones with risk of cerebral and myocardial infarctions in Japanese populations: The Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation. 2007;116:2553–62.

    CAS  PubMed  Google Scholar 

  9. 9.

    Yan Z, Zhang X, Li C, Jiao S, Dong W. Association between consumption of soy and risk of cardiovascular disease: A meta-analysis of observational studies. Eur J Prev Cardiol. 2017;24:735–47.

    PubMed  Google Scholar 

  10. 10.

    Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst. 2003;95:906–13.

    CAS  PubMed  Google Scholar 

  11. 11.

    Kurahashi N, Iwasaki M, Sasazuki S, Otani T, Inoue M, Tsugane S, et al. Soy product and isoflavone consumption in relation to prostate cancer in Japanese men. Cancer Epidemiol Biomark Prev. 2007;16:538–45.

    CAS  Google Scholar 

  12. 12.

    Shimazu T, Inoue M, Sasazuki S, Iwasaki M, Sawada N, Yamaji T, et al. Isoflavone intake and risk of lung cancer: A prospective cohort study in Japan. Am J Clin Nutr. 2010;91:722–8.

    CAS  PubMed  Google Scholar 

  13. 13.

    Yang W, Va P, Wong M, Zhang H, Xiang Y. Soy intake is associated with lower lung cancer risk: Results from a meta-analysis of epidemiologic studies. Am J Clin Nutr. 2011;94:1575–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Tse G, Eslick G. Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis. Eur J Nutr. 2016;55:63–73.

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhong X, Ge J, Chen S, Xiong Y, Ma S, Chen Q. Association between dietary isoflavones in soy and legumes and endometrial cancer: a systematic review and meta-analysis. J Acad Nutr Diet. 2018;118:637–51.

    PubMed  Google Scholar 

  16. 16.

    Nagata C, Wada K, Tamua T, Konishi K, Goto Y, Koda S, et al. Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study. Am J Clin Nutr. 2017;105:426–31.

    CAS  PubMed  Google Scholar 

  17. 17.

    Katagiri R, Sawada N, Goto A, Yamaji T, Iwasaki M, Noda M, et al. Association of soy and fermented soy product intake with total and cause specific mortality: prospective cohort study. BMJ. 2020.

  18. 18.

    Hwang C, Kwak H, Lim H, Lee S, Kang Y, Choe T, et al. Isoflavones metabolites and their in vitro dual functions: they can act as estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol. 2006;101:246–53.

    CAS  PubMed  Google Scholar 

  19. 19.

    Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol. 2009;55:361–6.

    CAS  PubMed  Google Scholar 

  20. 20.

    Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22:1428–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Murakami K, Yamanaka N, Ohnishi K, Fukayama M, Yoshino M. Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food. Food Funct. 2012;3:674–8.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wang H, Murphy P. Isoflavone content in commercial soybean foods. J Agric Food Chem. 1994;42:1666–73.

    CAS  Google Scholar 

  23. 23.

    Cederroth CR, Nef S. Soy, phytoestrogens and metabolism: a review. Mol Cell Endocrinol. 2009;304:30–42.

    CAS  PubMed  Google Scholar 

  24. 24.

    Clair RS, Anthony M. Soy, isoflavones and atherosclerosis. In: Handbook of experimental pharmacology. Heidelberg: Springer; 2005. p. 301–23.

  25. 25.

    Tsugane S, Sawada N. The JPHC Study: design and some findings on the typical Japanese diet. Jpn J Clin Oncol. 2014;44:777–82.

    PubMed  Google Scholar 

  26. 26.

    Tsubono Y, Takamori S, Kobayashi M, Takahashi T, Iwase Y, Litoi Youji, 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.

    CAS  PubMed  Google Scholar 

  27. 27.

    Yamamoto S, Sobue T, Sasaki S, Kobayashi M, Arai Y, Uehara M, et al. Validity and reproducibility of a self-administered food-frequency questionnaire to assess isoflavone intake in a Japanese population in comparison with dietary records and blood and urine isoflavone. J Nutr. 2001;131:2741–7.

    CAS  PubMed  Google Scholar 

  28. 28.

    Japan Science and Technology Agency. Standard tables of food composition in Japan. Fifth revised and enlarged edition. Tokyo: Ministry of Finance; 2005.

  29. 29.

    Kimira M, Arai Y, Shimoi K, Watanabe S. Japanese intake of flavonoids and isoflavonoids from foods. J Epidemiol. 1998;8:168–75.

    CAS  PubMed  Google Scholar 

  30. 30.

    Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N, et al. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr. 2000;130:2243–50.

    CAS  PubMed  Google Scholar 

  31. 31.

    Hirayama F, Lee AH, Binns CW, Watanabe F, Ogawa T. Dietary supplementation by older adults in Japan. Asia Pac J Clin Nutr. 2008;17:280–4.

    PubMed  Google Scholar 

  32. 32.

    Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:17–27.

    CAS  PubMed  Google Scholar 

  33. 33.

    Sasaki S, Kobayashi M, Tsugane S. Validity of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I: comparison with dietary records for food groups. J Epidemiol. 2003;13:S57–S63.

    PubMed  Google Scholar 

  34. 34.

    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:S134–47.

    PubMed  Google Scholar 

  35. 35.

    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:S115–24.

    PubMed  Google Scholar 

  36. 36.

    Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the world health organization Monica project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation. 1994;90:583–612.

    CAS  PubMed  Google Scholar 

  37. 37.

    Walker AE, Robins M, Weinfeld FD. The national survey of stroke. Clinical findings. Stroke. 1981;12:I13–44.

    CAS  PubMed  Google Scholar 

  38. 38.

    WHO. International classification of diseases for oncology. 3rd ed. Geneva: WHO; 2000.

    Google Scholar 

  39. 39.

    National Cancer Center Japan. Risk and protective factors for cancer. 2017.

  40. 40.

    The Official Journal of the Japan Atherosclerotic Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases. Guidelines for prevention of atherosclerotic CVD 2017. J Atheroscler Thromb. 2018;25:846–984.

    Google Scholar 

  41. 41.

    Tang J, Zheng JS, Fang L, Jin Y, Cai W, Li D. Tea consumption and mortality of all cancers, CVD and all causes: a meta-analysis of eighteen prospective cohort studies. Br J Nutr. 2015;114:673–83.

    CAS  PubMed  Google Scholar 

  42. 42.

    Nozue M, Shimazu T, Sasazuki S, Charvat H, Mori N, Mutoh M, et al. Fermented soy product intake is associated with the development of high blood pressure: the Japan public health center–based prospective study. J Nutr. 2017;147:1749–56.

    CAS  PubMed  Google Scholar 

  43. 43.

    Yang X, Nakamoto M, Shuto E, Hata A, Aki N, Shikama Y, et al. Associations between intake of dietary fermented soy food and concentrations of inflammatory markers: a cross-sectional study in Japanese workers. J Med Invest. 2018;65:74–80.

    CAS  PubMed  Google Scholar 

  44. 44.

    Uemura H, Katsuura-Kamano S, Nakamoto M, Yamaguchi M, Fujioka M, Iwasaki Y, et al. Inverse association between soy food consumption, especially fermented soy products intake and soy isoflavone, and arterial stiffness in Japanese men. Sci Rep. 2018.

  45. 45.

    Nestel P, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, et al. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol. 1997;17:3392–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Ma L, Liu G, Ding M, Zong G, Hu FB, Willett WC, et al. Isoflavone intake and the risk of coronary heart disease in US men and women: results from 3 prospective cohort studies. Circulation. 2020;141:1127–37.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    World Cancer Research Fund. Wholegrains, vegetables and fruit and the risk of cancer. London: World Cancer Research Fund; 2018.

    Google Scholar 

  48. 48.

    Hara A, Sasazuki S, Inoue M, Iwasaki M, Shimazu T, Sawada N, et al. Isoflavone intake and risk of gastric cancer: a population-based prospective cohort study in Japan. Am J Clin Nutr. 2012;95:147–54.

    CAS  PubMed  Google Scholar 

  49. 49.

    Akhter M, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Dietary soy and isoflavone intake and risk of colorectal cancer in the Japan public health center–based prospective study. Cancer Epidemiol Biomark Prev. 2008;17:2128–35.

    CAS  Google Scholar 

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JPHC members are listed at the following site (as of December 2019):


Supported by the National Cancer Research and Development Fund [23-A-31 (toku) and 26-A-2] (since 2010), a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010), a grant from commissioned project study, Ministry of Agriculture, Fishery and Forestry, Japan (JPJ005336).

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ST designed, initiated, and organized the study; MN analyzed the data; MN and TS wrote the paper; and TS had primary responsibility for final content. HC, NM, MM, NS, MIw, TY, MIn, YK, KY, and HI interpreted the data. All authors read and approved the final manuscript.

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Correspondence to Taichi Shimazu.

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Nozue, M., Shimazu, T., Charvat, H. et al. Fermented soy products intake and risk of cardiovascular disease and total cancer incidence: The Japan Public Health Center-based Prospective study. Eur J Clin Nutr 75, 954–968 (2021).

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