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Intake of Folate, Vitamin B₆ and Vitamin B₁₂ and the Risk of CHD: The Japan Public Health Center-Based Prospective Study Cohort I

Department of Public Health Medicine, Doctoral Program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki (J.I., H.I.)
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo (J.I., M.I., M.I., S.T.)
Public Health, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka (H.I.)
Department of Public Health, University of Ehime, Ehime (K.O.)
Department of Health Science, Shiga University of Medical Science, Shiga (Y.K.)
Department of Preventive Cardiology, National Cardiovascular Center, Osaka (Y.K., A.O.), JAPAN

Address correspondence to: Prof. Hiroyasu Iso, Public Health, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, JAPAN. E-mail: iso{at}pbhel.med.osaka-u.ac.jp

Address reprint requests to: Shoichiro Tsugane, MD, Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JAPAN. E-mail: stsugane{at}ncc.go.jp

	ABSTRACT

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Objective: To investigate the association of dietary folate, vitamin B₆ (VB₆) and vitamin B₁₂ (VB₁₂) with the risk of coronary heart disease among middle-aged persons.

Methods: A total of 40,803 subjects aged 40–59 years living in the community who were free of prior diagnoses of cardiovascular disease and cancer and who completed a food frequency questionnaire were followed from 1990–1992 to the end of 2001 in the Japan Public Health Center-based Prospective Study.

Results: After 468,472 person-years of follow-up, 251 coronary heart disease incidents were documented. Coronary heart disease and definite myocardial infarction were inversely associated with dietary intake of folate, VB₆ and VB₁₂ after adjustment for age and sex, but the associations were attenuated after further adjustment for smoking, dietary and other cardiovascular risk factors. However, among non-multivitamin supplement users, multivariable hazard ratios (95% confidence intervals) in the highest vs. lowest quintiles of VB₆ intake were 0.60 (0.37–0.97) for total coronary heart disease and 0.52 (0.29–0.91) for definite myocardial infarction, and the inverse associations with VB₁₂ were marginally significant. The combination of below-median intake of three vitamins or of only B₆ conferred a twice excess risk of total coronary heart disease.

Conclusions: Dietary intake of VB₆ was associated with a reduced risk of coronary heart disease among middle-aged non-multivitamin supplement users. Dietary folate and VB₁₂ were also suggested to be protective factors for coronary heart disease.

Key words: folate, vitamin B₆, vitamin B₁₂, coronary disease, diet

Abbreviations: CHD=coronary heart disease • CI=confidence interval • FFQ=food frequency questionnaire • HR=hazard ratio • VB₆=vitamin B₆ • VB₁₂=vitamin B₁₂

	INTRODUCTION

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Folate, vitamin B₆ and vitamin B₁₂ are important enzymatic cofactors in the synthesis of methionine from homocysteine[1,2], and a deficiency in any of them raises homocysteine concentrations in the blood [3–8]. Because increased homocysteine is associated with cardiovascular disease, a protective effect for folate, vitamin B₆ and vitamin B₁₂ has been hypothesized and investigated. Some [9,10] but by no means all [11–14] prospective studies have shown an inverse association between blood concentrations of these vitamins and the risk of cardiovascular disease. However, evidence that the dietary intake of B vitamins is a protective risk factor for cardiovascular disease remains limited. A few prospective epidemiological studies in Western populations have reported an inverse association between dietary folate and coronary heart disease (CHD) [15–17], and one of these also reported a protective effect of dietary vitamin B₆ [15]. No associations have been found for vitamin B₁₂, and few studies have examined the potential effect of the combination of these vitamins [17]. Supplementation with these nutrients was shown to lower homocysteine levels in a number of clinical trials [18], but an effect of supplementation on secondary prevention of CHD or stroke has also been inconsistent [19–26]. To our knowledge, moreover, no evidence has been provided for a protective effect of these B vitamins in Asian populations.

We therefore investigated the relationship of dietary intakes of folate, vitamin B₆ and vitamin B₁₂ with risk of CHD in a large prospective follow-up study of middle-aged Japanese men and women. Further, we also investigated the effect of the combination of these vitamins in protection against CHD.

	METHODS

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Study Cohort
The Japan Public Health Center-based Prospective Study (JPHC Study) Cohort I was a population-based sample of 27,063 men and 27,435 women born between 1930 and 1949 (40–59 years of age) and registered as of January 1, 1990 as residents of 14 administrative districts supervised by four public health center (PHC) areas in Japan. These areas included Ninohe City and Karumai town in the Ninohe PHC area of Iwate Prefecture, Yokote City and Omonogawa town in the Yokote PHC area of Akita, eight districts of Minami Saku county in the Saku PHC area of Nagano, and Gushikawa City and Onna village in the Chubu (previously named Ishikawa) PHC area of Okinawa [27]. The present study was approved by the Institutional Ethical Review Committees of the National Cancer Center and University of Tsukuba.

Exposure Assessment
A self-administered questionnaire was handed out (partially mailed) to all registered non-institutional residents through each PHC in 1990. Of these, 20,665 men (76 percent) and 22,484 women (82 percent) returned the questionnaire between February 1990 and October 1990. Data was collected on demographic characteristics, medical history, smoking and drinking habits, and frequency of intake for 44 food-items (1990 FFQ). In 1995, a second questionnaire (1995 FFQ), which included 147 food items, was also handed out (partially mailed) through the PHC to the same participants. Among those who responded the 1990 FFQ, 80 percent men and 86 percent women responded to the 1995 FFQ. Exposure variables including dietary intake according to the 1990 FFQ was updated by the 1995 FFQ.

Each participant was asked how often on average during the previous month (1990 FFQ) or year (1995 FFQ) he or she had consumed specific foods and beverages. A common unit or portion size for each food was specified in the 1995 FFQ but not in the 1990 FFQ. Responses were possible for each food item, ranging from "rarely’, "1–2 days/week’, "3–4 days/week’, and ‘almost every day’ in the 1990 FFQ, and from "rarely’, "1–3 days/month’, "1–2 days/week’, "3–4 days/week’, and "5–6 days/week’, "once/day’, "2–3 times/day’, "4–6 times/day’, and "7 or more times/day’ in the 1995 FFQ. The amount of each food consumed was calculated by multiplying the frequency of consumption of each food (0, 1.5, 3.5, and 6.0, respectively, in the 1990 FFQ, and 0, 0.07, 0.2, 0.5, 0.8, 1.0, 2.5, 5.0 and 8.0, respectively, in the 1995 FFQ) with the respective portion sizes as estimated by a validation study conducted in a sample of 94 men and 107 women selected from cohort subjects in the 1990 FFQ [28] and the pre-determined portion size in the 1995 FFQ [29]. The daily intake of nutrients including folate, vitamin B₆ and vitamin B₁₂ for individuals was calculated using the Standardized Tables of Food Composition, 5th ed. [30] Intake of folate, vitamin B₆ and vitamin B₁₂ was adjusted for total energy intake by the sex- and FFQ-specific residual model. Enquiry on the use of multivitamin supplements was made in both FFQs, but intake from supplements was not included in analysis because no comprehensive database for supplements was available.

A validation study was conducted to test the validity and reproducibility of both the 1990 and 1995 FFQs [31]. Validity of the 1995 FFQ in assessing folate, vitamin B₆ and vitamin B₁₂ intake was evaluated against 7-day dietary records collected in each of the 4 seasons as the objective standard. Mean intakes of folate, vitamin B₆ and vitamin B₁₂ estimated by the 1990 FFQ were slightly underestimated, but those by the 1995 FFQ were closely similar to the estimated objective standards. Validity of the dietary measurement of folate, vitamin B₆ and vitamin B₁₂ by the 1990 FFQ was moderate to low (deattenuated Spearman's correlation coefficients for energy-adjusted value=0.18, 0.39 and 0.48 for men, respectively, and 0.07, 0.03 and 0.48 for women, respectively), while that by the 1995 FFQ was high (deattenuated Spearman's correlation coefficients for energy-adjusted value=0.57, 0.59 and 0.51 for men, respectively, and 0.47, 0.63 and 0.58 for women, respectively). Validity of 1995 FFQ tested using plasma concentrations as references was moderate for folate and vitamin B₆ (r=0.26 and 0.23, respectively), and low for vitamin B₁₂ (r=0.06) [32], which may be because total plasma level of vitamin B₁₂ is not a sensitive indicator of intake [33,34]. Regarding reproducibility, the Spearman correlation coefficient between two questionnaires administered 5–6 years apart was 0.48, 0.34 and 0.19 for folate, vitamin B₆ and vitamin B₁₂ intake, respectively, for the 1990 FFQ. For the 1995 FFQ, the coefficient for two questionnaires administered 1 year part was 0.45, 0.30 and 0.45 for folate, vitamin B₆ and vitamin B₁₂ intake, respectively.

Confirmation of CHD
We registered a total of 30 hospitals with departments of cardiology in the four PHC areas. All were major hospitals in their area to which patients with acute CHDs would likely be admitted. In each hospital, medical records were reviewed by registered staff physicians or PHC physicians who were blinded to the lifestyle data. Acute coronary events were registered if they occurred after the date of return of the baseline questionnaire and before January 1, 2002.

Myocardial infarction was confirmed in the medical records according to the criteria of the MONICA project [35], which stipulates electrocardiographic, cardiac enzyme and autopsy evidence, either alone or in combination. When such work-up was not performed but typical chest pain was present, a diagnosis of probable was made. For sudden death of unknown origin, deaths that occurred within 1 h of onset were regarded as sudden cardiac death.

To complete the surveillance for nonfatal myocardial infarction (MI), we made inquiries by letter or telephone about the onset of coronary events and for permission to review the medical records to 141 subjects who reported a history of MI on the 10-year follow-up questionnaire (88% response rate) which had not been otherwise registered as a coronary event. Of these 141 individuals, 122 (87 percent) were contacted and 74 provided information on suspected MI. Of these 74, 63 (85 percent) provided written informed consent to review of their medical records, which was done by the relevant hospital staff physician, or by PHC or research physicians.

For fatal MI and sudden cardiac deaths [International Classification of Diseases, 10th Revision (ICD-10) 121–123, 146 and 150], we conducted a systematic search of death certificates. Death certificates were forwarded to the PHC in the area of residence, and mortality data were sent centrally to the Ministry of Health, Welfare and Labor and coded for the National Vital Statistics. Registration of death is required by the Family Registration Law, and the registry is believed to be complete in Japan.

Statistical Analysis
We further excluded from analysis individuals who reported MI, angina pectoris, stroke or cancer at baseline, and who under- or over-reported energy intake in the 1990 or 1995 FFQ, i.e., <1% and >99% of energy intake calculated separately for each sex and FFQ. A total of 40,805 subjects were included in the analysis. Statistical analyses were based on incidence rates of CHD during up to 12-year follow-up (mean follow-up time was 11.5 years). For each individual, person-months of follow-up were calculated from the day of return of the initial questionnaire to the first endpoint, death, relocation of residency out of the study area or January 1, 2002, whichever came first.

Participants were divided into quintiles of folate, vitamin B₆ and vitamin B₁₂ intake according to separate cutoff point for 1990 and 1995 FFQ. To allow participants to change exposure status in 5 years, person-month before the return of 1995 FFQ was allocated to category of nutrient intake according to 1990 FFQ, and person-month after that was allocated to category of nutrient intake according to 1995 FFQ. For participants who did not respond to 1995 FFQ, categories according to the 1990 FFQ were carried forward.

The hazard ratio with 95% confidence intervals (CI) was calculated after adjustment for age and other potential confounding factors using the time-dependent Cox proportional-hazards model. Potential confounding factors for adjustment were baseline values of age (5-year), smoking status (never, ex-, current 1–19, and current 20+ cigarettes per day), alcohol intake [nondrinkers (<1 day per month), occasional drinkers (1–3 days per month), weekly ethanol intake of 1–149 g/week, 150–299 g/week, 300–449 g/week, and 450 g/week], body mass index (quintiles), histories of hypertension and diabetes (no and yes), medication for hypercholesterolemia (no and yes), education level (junior high school, high school, and college or higher), sports at leisure time (< 1 day/month, 1–3 days/month and 1 day/week), use of multivitamin supplements (no and yes), and quintiles of dietary intake of saturated fat, monounsaturated fat, n-6 and n-3 polyunsaturated fat, cholesterol and total energy.

We also calculated the hazard ratio among those who did not use multivitamin supplements (n=37,477). Further, the effect of the combination of these B vitamins on CHD among those who did not use multivitamin supplements was tested. For this, we categorized individuals into one of two groups, namely high (above median) and low (median or lower) intake according to intake of each vitamin, and made 8 combinations of B vitamin intake. Multivariable hazard ratio with 95% CI of CHD was calculated for each combination using those who had high levels of all 3 vitamins as reference. A test for trends across the categories of folate, vitamin B₆ or vitamin B₁₂ was conducted by assigning median values for each category and testing significance for the respective variable. Interaction with smoking, alcohol or other B vitamins such as B₆ and vitamin B₁₂ was tested using an interaction term generated by multiplying the median of each quintile of the B vitamin by smoking (current or no smoker), alcohol (< or >=1/week) or nutrient intake (over or below median). SAS Version 8.02 (SAS Institute Inc., Cary, NC) was used to perform all statistical analyses.

	RESULTS

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During 468,472 person-year follow-up of 40,803 middle-aged subjects (19,343 men and 21,460 women), we documented 251 incident cases of CHD (201 men and 50 women), including 192 definite MIs (153 men and 39 women). Median ages of subjects at recruitment to the cohort were 50 years-old. Median age of subjects at recruitment to the cohort and/or at diagnosis with CHD was 60 years-old. Table 1 shows cardiovascular risk factors and intake of selected nutrients and foods, by dietary intake of folate, vitamin B₆, and vitamin B₁₂. Compared with individuals who consumed less folate, individuals who consumed more were slightly older; and also more likely to have a history of diabetes, be under treatment for hyperlipidemia, exercise, and have regular multivitamin supplement intake. Individuals who consumed more vitamin B₆ were, in addition to the factors associated with folate, also more likely to have a higher alcohol intake, less likely to be current smokers, more likely to be hypertensive, and have a higher education level. Individuals who consumed more vitamin B₁₂ were also similar to those who consumed more folate, but were more likely to have a higher alcohol intake, to be current smokers, and hypertensive. Dietary intakes of folate, vitamin B₆ and vitamin B₁₂ intake were positively associated with intake of total energy, saturated, monounsaturated, n-3 and n-6 unsaturated fatty acids, cholesterol, fish, meat, dairy products, fruits and vegetables. Mean dietary intakes of folate, vitamin B₆ and vitamin B₁₂ in the lowest quintile were 290 µg, 1.30 mg and 6.5 µg per day, respectively, whereas those of each nutrient in the highest quintiles were 436 µg, 1.60 mg and 11.1 µg.

Fig. 1 illustrates the hazard ratios for the combination of B vitamin intakes with reference to the above-median intake of all three vitamins among non-multivitamin supplement users. Individuals who had below-median levels of dietary vitamin B₆ tended to have a 1.5 to 2 times higher risk of definite MI. Below-median intake of all three vitamins conferred a excess risk of definite MI [hazard ratio (CI)=2.13 (1.31–3.48)]. For persons who had below-median levels of vitamin B₆, but above-median levels of both folate and vitamin B₁₂, there also was a significant excess risk of definite MI [hazard ratio (CI)=2.16 (1.15–4.41)].

View larger version (9K): [in this window] [in a new window]   Fig. 1. Multivariable hazard ratios [HR] (95% CI) of definite MI among non-multivitamin users by combinations of folate, vitamin B6 and vitamin B12 intake below or above the respective median values.

	DISCUSSION

Several prospective studies have identified an inverse association between dietary folate and CHD. In 1998, Rimm et al. found an approximately 30% lower risk of CHD in nurses who consumed higher levels of dietary and supplemental folate (median intake = 696 µg/day) compared to those who consumed lower levels (median intake=190 µg/day) [15]. They also showed a 30% lower risk in those who consumed higher levels of vitamin B₆ (median intake =4.6 mg/day) compared to those who consumed lower levels (median intake=1.1 mg/day). The range of folate and vitamin B₆ intake was large in their study because the major sources of study nutrients were multiple vitamins and fortified breakfast cereals, which contained high levels of these nutrients. Further, they identified the use of multiple vitamin supplements of 4–7 pills per week as protective for CHD. In 2001, Voutilainen et al. reported a 55% lower risk of acute coronary events in middle-aged Finnish men who consumed moderate levels of folate (>297 µg/day) than in those with low intake (<211 µg/day), but associations with vitamin B₆ and B₁₂ were null or weak [17]. In the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study [16], Bazzano et al. reported an approximately 10% lower risk of CHD in those who consumed moderate levels of dietary folate (>301 µg/day) than in those with low intake (<136 µg/day).

In the present study, the strong inverse association was observed between dietary vitamin B₆ and risk of CHD and MI when the subjects were limited to those who did not use multivitamin supplements. These inverse associations might have been reinforced by the low vitamin B₆ exposure range in this population. Dose-response relationships between nutrients and health are clear when intake is deficient to marginal, but somewhat flat for exposure within the optimal range [36]. The mean dietary vitamin B₆ intake in the highest quintile in our population (1.60 mg/day) is lower than the mean intake of the lowest quintile (1.65 mg/day) in the Finnish men's study, which reported no association [17]. A strong inverse association between plasma vitamin B₆ levels and risk of CHD in Americans was also reported by Folsom et al. [37]. Low serum folate concentrations are associated with an increased risk of cardiovascular disease or CHD [38,39].

Possible perspective on our results for the combination of B vitamins is that insufficient intake of one of these nutrients is associated with higher incidence of MI. In our population with low vitamin B₆ levels, but somewhat sufficient levels of folate and vitamin B₁₂, low intake of vitamin B₆ was associated with increased risk of MI even under the condition of high intake of other 2 nutrients. When either folate or vitamin B₁₂ intake was low, on the other hand, no association with MI was seen. Folate is a one-carbon donor for the re-methylation of homocysteine to methionine [1]. Vitamins B₆ and B₁₂ are involved in this folate metabolism pathway [40]: vitamin B₆ works as a cofactor for cystathionine-β-synthase, which catalyzes the conversion of homocysteine to cystathionine, and also as a cofactor in the conversion of tetrahydrofolate to 5,10-methylene tetrahydrofolate, while vitamin B₁₂ works as a cofactor for methionine synthase, which re-methylates homocysteine to methionine. Homocysteine may promote atherogenesis by damaging the vascular matrix, increasing the proliferation of endothelial cells and facilitating oxidative injury to vascular walls [41,42]. A deficiency in any of these nutrients thus results in the accumulation of homocysteine. Importantly, however, the intake of vitamin B₁₂ is not the sole determinant of physiological level: absorption and utilization also play a role [34], and we assume that individual variation in these factors explains why the association was not as strong for vitamin B₁₂.

Mainstream thought has recently focused on the etiological role in CHD of deficiencies in specific nutrients [43]. Our study suggested the possibility that CHD may be caused by insufficient B vitamin intake, in part through high blood levels of homocysteine. Our results also support the finding of the Nurses’ Health Study that a strong inverse association exists between dietary folate and risk of coronary heart disease, primarily in smokers [15]. This result is biologically plausible since folate may protect the vascular wall from the radical damage derived from smoking [44]. Thus, even though the inverse association was not significant in the overall population, folate would play an important role in preventing CHD in smokers.

Dietary folate in our population was derived from various foods of both plant and animal origin, such as spinach, rice, green tea, cabbage and eggs, with green tea the greatest contributor to between-person variability (9.6% of total variability) [45]. Major sources of vitamin B₆ were rice, tuna fish, potatoes, beer and sake (Japanese rice-wine), with rice the greatest contributor to variability (11.5% of total variability), while vitamin B₁₂ was primarily from various types of fish, with fish thus the greatest contributor to between-person variability (17.9% of total variability). Very few foods are fortified with these nutrients in Japan. We investigated the association between the dietary intake of those foods that contribute to B vitamin intake and the risk of CHD, but found no association except for fish [46], probably because B vitamins are widely sourced from many foods rather than a few particular foods, and so the association with any particular food is weak.

The present study has several limitations. First, it is possible that individuals who had a high intake of folate, vitamin B₆ and vitamin B₁₂ were at lower risk of CHD due to other health habits and behaviors. The likelihood of this was reduced, however, by the multivariable adjustment for a number of potential confounding variables including traditional cardiovascular risk factors, physical activity, alcohol intake, selected dietary variables, total energy intake and multivitamin use, all of which had only a small effect on the associations observed. Second, measurement errors in assessing nutrient intake are inevitable. Although the 1995 FFQ provided reasonable measurement, the lower validity of the 1990 FFQ, especially for folate, may have resulted in the misclassification of individual intake. Statistically, however, such random errors of measurement tend to result in null rather than spurious associations. To confirm a lack of effect, we conducted a subanalysis using data derived after 1995; results showed a similar association for B vitamins, but without significance due to a lack of power. Third, owing to the lack of a suitable database, individual intake did not take account of the nutrient content of vitamin supplementation. Any such influence on folate intake was assumed to be negligible, however, because very few folic acid supplements were available in the Japanese market at the time of the study. Generally, vitamin B₆ and B₁₂ supplementation in Japan is via multivitamin tablets and supplement drinks. The exclusion of users of multivitamin supplements here deattenuated the hazard ratios substantially, but the effects of high-dose supplemental B vitamins on cardiovascular disease and of dietary intake of B vitamins by supplement users remain uncertain. Fourth, the power limitations prevented the sex-specific analysis, primarily in women whose incidence of CHD was a lot fewer than men. Fifth, the interpretation of findings on vitamin B₁₂ intake needs to be made carefully by reference to blood levels, given that the true physiologic level is determined not only by ingestion but also by absorption and utilization [34]. We are now preparing a nested case-control study among the JPHC Study participants to investigate the relationship between plasma vitamin B levels and risk of CHD.

In conclusion, dietary intake of vitamin B₆ was associated with a reduced risk of CHD among middle-aged non-multivitamin users. Dietary folate and vitamin B₁₂ were also suggested to be protective factors for CHD.

	ACKNOWLEDGMENTS

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This study was supported by Grants-in-aid for Cancer Research and for the 3rd Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan. Junko Ishihara is an Awardee of a Research Resident Fellowship from the Foundation for the Promotion of Cancer Research (Japan) for the 3rd Term Comprehensive 10-year Strategy for Cancer Control. The authors thank all staff members in each study area and in the central office for their painstaking efforts in conducting the baseline survey and follow-up. The authors would like to acknowledge the members of JPHC Study Group: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, Niigata Prefectural Kashiwazaki Public Health Center, Kashiwazaki; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; S. Watanabe, M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi Medical School, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; M. Yamaguchi, Y. Matsumura, S. Sasaki, National Institute of Health and Nutrition, Tokyo; and T. Kadowaki, Tokyo University, Tokyo.

Received April 12, 2006. Accepted November 4, 2006.

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