Dietary Folate and Vitamin B6 and B12 Intake in Relation to Mortality From Cardiovascular Diseases
Japan Collaborative Cohort Study
Background and Purpose— The association of dietary folate and B vitamin intakes with risk of cardiovascular disease is controversial, and the evidence in Asian populations is limited.
Methods— A total of 23 119 men and 35 611 women, age 40 to 79 years, completed a food frequency questionnaire in the Japan Collaborative Cohort Study. During the median 14-year follow-up, there were 986 deaths from stroke, 424 from coronary heart disease, and 2087 from cardiovascular disease.
Results— Dietary folate and vitamin B6 intakes were inversely associated with mortality from heart failure for men and with mortality from stroke, coronary heart disease, and total cardiovascular disease for women. These inverse associations did not change materially after adjustment for cardiovascular risk factors. No association was found between vitamin B12 intake and mortality risk.
Conclusions— High dietary intakes of folate and vitamin B6 were associated with reduced risk of mortality from stroke, coronary heart disease, and heart failure among Japanese.
Folate, vitamin B6, and vitamin B12 are cofactors in homocysteine metabolism, and low intakes of these nutrients are associated with higher blood homocysteine concentrations, a potential risk factor for coronary heart disease (CHD) and stroke.1 However, the effect of supplementation with these nutrients on secondary prevention of CHD or stroke has been controversial.2,3 Furthermore, the evidence for an association between dietary intakes of folate and B vitamins and risk of cardiovascular disease (CVD) in Asian populations remains limited. No investigators have prospectively examined the associations of these vitamin intakes with heart failure, although blood homocysteine concentrations higher than the median (≥11.8 mmol/L for men and ≥11.1 mmol/L for women) were associated with a 2-fold increased risk.4 There is thus an urgent need for a prospective study to replicate previous results in different populations and validate the associations.
Subjects and Methods
The Japan Collaborative Cohort Study began in 1988 to 1990.5 The data from food frequency questionnaires were available for 24 386 men and 37 493 women age 40 to 79 years at baseline. We excluded persons who self-reported a history of CVD (n=2294) and cancer (n=855) at baseline because they were likely to change their dietary habits. The remaining 23 119 men and 35 611 women were enrolled in our study. The ethics committees of the Nagoya University School of Medicine and Osaka University Graduate School of Medicine approved the present study.
Exposure Assessment and Mortality Surveillance
The method for mortality surveillance has been described in detail elsewhere.5 The underlying causes of death were determined according to the International Classification of Diseases, 10th revision, as follows: death from stroke (ICD I60-I69), CHD (ICD I20-I25), heart failure (ICD I50), and CVD (ICD I01-I99). Follow-up was conducted until the end of 2003, except for 4 communities, in which follow-up ended in 1999.
The daily intake of nutrients for individuals was calculated by consulting the Standardized Tables of Food Composition, 5th ed.6 Intakes of folate and vitamin B6 were adjusted for total energy intake by means of a sex-specific residual model to reduce the influence of energy intake.
The hazard ratios and their 95% CIs of mortality outcomes according to quintiles of dietary intakes of folate (<272, 272–351, 352–430, 431–535, and ≥536 μg/d), vitamin B6 (<0.79, 0.79–0.96, 0.97–1.11, 1.12–1.32, and ≥1.33 mg/d), and B12 (<4.5, 4.5–5.9, 6.0–7.6, 7.7–9.8, and ≥9.9 μg/d) were calculated by using the Cox proportional-hazards model.
The confounding variables comprised age (year), body mass index (sex-specific quintiles), smoking status (never, ex-smoker, and current smoker of 1–19 and ≥20 cigarettes/d), alcohol intake category (never, ex-drinker, and current drinker of 1–22, 23–45, 46–68, and ≥69 g of ethanol per day), history of hypertension and diabetes (yes), as well as saturated fatty acids and n-3and n-6 polyunsaturated fatty acids (sex-specific quintiles). SAS version 9.1 (SAS Institute Inc, Cary, NC) was used to perform all statistical analyses (2 tailed).
Table 1 shows baseline characteristics according to quintiles (lowest, middle, and highest) of dietary folate and vitamin B6 and B12 intakes. During the median 14-year follow-up, we documented 986 (500 in men and 486 in women) deaths from stroke, 424 (233 in men and 191 in women) from CHD, 318 (151 in men and 167 in women) from heart failure, and 2,087 (1066 in men and 1021 in women) from CVD.
Dietary folate and vitamin B6 intakes were inversely associated with mortality from heart failure for men and with mortality from stroke, CHD, and total CVD for women (Table 2⇓). These inverse associations did not change materially after adjustment for CVD risk factors.
When we excluded the subjects who were using multivitamin supplements (n=7334), the results did not change materially. For example, the multivariable hazard ratios (and 95% CIs) of CHD for the highest versus lowest quintiles were 0.62 (0.42–0.89) for folate, 0.51 (0.29–0.91) for vitamin B6, and 1.35 (0.80–2.27) for vitamin B12 intakes and those for heart failure were 0.76 (0.51–1.13) for folate, 0.60 (0.32–1.13) for vitamin B6, and 1.57 (0.90–2.73) for vitamin B12 (data not shown).
We found inverse associations between folate and vitamin B6 intakes and risk of mortality from stroke and CHD for Japanese, which are consistent with previous reports of these associations for Americans7 and Europeans.8
Furthermore, this study is the first to show that high dietary intakes of folate and vitamin B6 were associated with a reduced risk of heart failure mortality for men. Mechanisms for these observed associations may involve the effects of these vitamin intakes on reductions of blood homocysteine concentrations. A meta-analysis of observational studies provided evidence that a 3-μmol/L reduction in homocysteine level was associated with an 11% reduction in CHD risk and a 19% reduction in stroke risk.1 A single, large, clinical trial of women, however, did not show any beneficial effect of folic acid supplementation on risk of CVD.2 A more recent clinical trial of men and women has demonstrated that the lowering of homocysteine by supplementation with folic acid, vitamin B6, and vitamin B12 reduced the risk of stroke.3 Taken together, our results suggest that dietary intakes of folate and vitamin B6 may be useful to prevent CVD.
The supplementation with folate and vitamin B6 was not taken into account in the present study, but the observed associations did not change after exclusion of persons who were taking multivitamin supplements. Also, we used the mortality data as end points, which may have led to misclassification in the diagnosis of stroke, CHD, and heart failure. However, previous validation studies indicated the validity of death certificate diagnoses for these outcomes because of the widespread use of computed tomography or magnetic resonance imaging for stroke diagnosis9 and of ECG and cardiac enzyme examinations for CHD and heart failure.10
In summary, high dietary folate and vitamin B6 intakes were associated with a reduced risk of mortality from stroke, CHD, and heart failure among Japanese.
The authors thank all members of the Japan Collaborative Cohort Study, which is available in detail at: http://www.aichi-med-u.ac.jp/jacc/member.html.
Sources of Funding
This study was supported by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho) and the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Monbu-kagaku-sho): grant numbers 61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, 11181101, 18014011, 20014026, 17015022, 18014011, 14207019 and 19390174.
- Received January 11, 2010.
- Revision received February 2, 2010.
- Accepted February 9, 2010.
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