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American Journal of Epidemiology Advance Access originally published online on October 10, 2007
American Journal of Epidemiology 2008 167(1):59-70; doi:10.1093/aje/kwm263
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Fruit and Vegetable Intake and Risk of Total Cancer and Cardiovascular Disease

Japan Public Health Center-based Prospective Study

Ribeka Takachi1,2, Manami Inoue2, Junko Ishihara2, Norie Kurahashi2, Motoki Iwasaki2, Shizuka Sasazuki2, Hiroyasu Iso3, Yoshitaka Tsubono1,4, Shoichiro Tsugane2 and for the JPHC Study Group

1 Department of Clinical Epidemiology, Tohoku University Graduate School of Medicine, Sendai, Japan
2 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
3 Public Health, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
4 Division of Health Policy, Tohoku University School of Public Policy, Sendai, Japan

Correspondence to Dr. Shoichiro Tsugane, 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).

Received for publication April 5, 2007. Accepted for publication August 17, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Few studies have investigated the effects of fruit and vegetables on the risk of both cancer and cardiovascular disease (CVD). The authors examined associations between fruit and vegetable consumption and risk of total cancer and CVD in the same Japanese population. During 1995–1998, a validated food frequency questionnaire was administered in nine areas to 77,891 men and women aged 45–74 years. During as many as 459,320 person-years of follow-up until the end of 2002, 3,230 cancer cases and 1,386 CVD cases were identified. Higher consumption of fruit, but not vegetables, was associated with significantly lower risk of CVD: multivariate hazard ratios for the highest versus lowest quartiles of intake were 0.81 (95% confidence interval (CI): 0.67, 0.97; trend p = 0.01) for fruit and 0.97 (95% CI: 0.82, 1.15; trend p = 0.66) for vegetables. Consumption of fruit or vegetables was not associated with decreased risk of total cancer: corresponding hazard ratios were 1.02 (95% CI: 0.90, 1.14; trend p = 0.95) for fruit and 0.94 (95% CI: 0.84, 1.05; trend p = 0.16) for vegetables. This prospective cohort study demonstrated that, in the Japanese population, consumption of fruit is associated with lower risk of CVD, whereas fruit or vegetables may not be associated with lower risk of total cancer.

cardiovascular diseases; fruit; Japan; neoplasms; prospective studies; vegetables

Abbreviations: CI, confidence interval; CVD, cardiovascular disease; FFQ, food frequency questionnaire; HR, hazard ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Cancer and cardiovascular disease (CVD) are the leading causes of death in many parts of the world. It has been suggested that fruit and vegetable consumption protects against both (1–8), but associations with site-specific cancers have been controversial in recent prospective cohort studies (9–20), most of which evaluated fruit and vegetable consumption in relation to the risk of cancer or CVD separately.

One approach to determining the net impact of fruit and vegetable consumption on disease prevention is to examine associations of fruit and vegetable consumption with risk of cancer and CVD simultaneously in the same population. To our knowledge, six such prospective cohort studies have been reported, and they found inverse associations that were more consistent for CVD than for total cancer (21–26). However, all of the studies were conducted in Western populations (United States (21, 24, 25), United Kingdom (22), Sweden (23), and Finland (26)), and we know of no data reported for Asian populations. Asian populations tend to differ from Western populations with respect to the distributions of exposure (consumption of higher vegetable and lower fruit amounts), outcome (higher incidence of infection-related cancers and stroke and lower incidence of hormone-related cancers and coronary heart disease), and covariates (higher prevalence of smoking and lower prevalence of obesity and low fat intake). Therefore, similar studies in Asian populations are important to better characterize the overall impact of fruit and vegetable consumption on the global burden of cancer and CVD.

In this study, we used a validated comprehensive food frequency questionnaire (FFQ) to examine associations between fruit and/or vegetable consumption and risk of cancer and CVD in a population-based prospective cohort study in Japan. Both total cancer and CVD incidence were the endpoints.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Japan Public Health Center-based Prospective Study was conducted on two cohorts, one initiated in 1990 (cohort I) and the other in 1993 (cohort II). The study design has been described in detail previously (27). The study protocol was approved by the institutional review board of the National Cancer Center, Tokyo, Japan.

The study population was defined as all registered Japanese inhabitants in 11 public health center areas, aged 40–59 years in cohort I and 40–69 years in cohort II. The Japanese inhabitants were identified by the population registries maintained by the local municipalities. Two public health center areas (Tokyo and Osaka) were excluded from the present analysis because either cancer or CVD incidence data were not available.

Surveys of the cohort participants by self-administered questionnaire were conducted twice, the first in 1990 (cohort I) and 1993 (cohort II) and the second in 1995 (cohort I) and 1998 (cohort II). Since the second survey questionnaire included more comprehensive information on food intake frequency than the first, the second survey was used as the starting point to assess dietary exposure in the present study. The questionnaire also included other items on medical history and lifestyle factors, such as smoking and alcohol drinking.

The remaining 114,865 subjects at the starting point were eligible as the study population after we excluded the 1,807 persons who had died, moved out of a study area, or were lost to follow-up before the starting point. A total of 91,103 subjects (42,708 men, 48,395 women) responded, yielding a response rate of 79.3 percent, and were included in the present study.

Food frequency questionnaire
The FFQ included 138 food and beverage items with standard portions/units and nine frequency categories. The FFQ asked about usual consumption of 16 fruits and 30 vegetables during the previous year. The fruit items included three citrus fruits (mandarin oranges, other oranges, and 100 percent orange juice) and 13 other fruits (papaya, apples, persimmons, strawberries, grapes, melons, watermelon, peaches, pears, kiwi fruit, pineapple, bananas, and 100 percent apple juice). The vegetable items included six pickled vegetables (Chinese radishes, green leafy vegetables, plums, Chinese cabbage, cucumbers, and eggplant), seven cruciferous vegetables (cabbage, Chinese radishes, komatsuna, broccoli, Chinese cabbage, leaf mustard, and chard or Swiss chard), six green leafy vegetables (spinach, Chinese chives, garland chrysanthemums, chingensai, mugwort, and green pepper), four yellow vegetables (carrots, tomatoes, pumpkins, and tomato juice), and seven other vegetables (onions, cucumbers, bean sprouts, snap beans, lettuce, bitter gourds, and loofah).

The questionnaire contained nine frequency categories for fruits and vegetables other than 100 percent orange juice, 100 percent apple juice, and tomato juice, ranging from "almost never" to "7 or more times per day." Standard portion sizes were specified for each food item, and there were three choices of amounts: small (50 percent smaller), medium (same as the standard), and large (50 percent larger). Nine frequency choices for juice ranged from "almost never" to "10 or more glasses per day." The amounts of fruit (grams/day) and vegetables (grams/day) consumed were calculated from the responses. We documented the validity of the FFQ for assessment of fruit and vegetable consumption (28, 29): the Spearman's correlation coefficients between energy-adjusted consumption based on the FFQ and those based on 28-day (or 14-day for the Ishikawa public health center area) dietary records among subsamples of men and women were 0.57 and 0.34 for fruit and 0.38 and 0.44 for vegetables, respectively. The correlation coefficients for the reproducibility of the FFQ administered 1 year apart for men and women were 0.57 and 0.53 for fruit and 0.59 and 0.59 for vegetables, respectively (29, 30).

Follow-up
Subjects in cohort I were followed from 1995, and subjects in cohort II were followed from 1998, until December 31, 2002. Changes in residence status including survival were obtained annually from the residential registry in each area or, for those who had moved out of the study area, through the municipal office in the area to which they had moved. Mortality data for persons in the residential registry are forwarded to the Ministry of Health, Labour and Welfare and are coded for inclusion in the national Vital Statistics. Residency registration and death registration are required by the Basic Residential Register Law and Family Registry Law, respectively, and are thought to be complete. During the follow-up period in the present study, 3,782 subjects (4.2 percent) died, 2,056 (2.3 percent) moved out of the study area, and 14 persons (0.02 percent) were lost to follow-up.

The occurrence of cancer was identified by active patients' notification from major local hospitals in the study area and from data linkage with population-based cancer registries, with permission from each of the local governments responsible for the cancer registries. Cases of cancer were coded according to the International Classification of Diseases for Oncology, Third Edition (31). In our cancer registry system, the proportion of cases for whom information was available from death certificates only was 4.5 percent. Diagnoses of myocardial infarction according to the criteria of the MONICA project (32) and diagnoses of stroke by computer tomographic scan and/or magnetic resonance imaging according to the criteria of the National Survey of Stroke (33) were confirmed, for all the cases, in the medical records reviewed by hospital or public health center physicians in each registered major local hospital in each public health center area (34, 35). CVD cases with a death certificate or self-report only, without confirmation by medical records, were excluded. CVD was defined as myocardial infarction or stroke, whichever occurred first. We confirmed 5,521 cases of newly diagnosed cancers and 2,426 cases of CVD among the 91,103 subjects by December 31, 2002.

Statistical analysis
Of the 91,103 respondents, we excluded subjects who did not complete the diet part of the questionnaire (n = 1,702) and those with a past history of cancer or coronary heart disease and/or stroke (n = 8,127). Subjects with a past history were defined as those diagnosed with cancer or CVD before the starting point or from self-reports in the questionnaire. Of the 81,989 subjects, 4,098 who reported extreme total energy intake (lower and upper 2.5 percentiles, 883 and 3,981 kcal/day, respectively) were excluded. Thus, 77,891 subjects (35,909 men, 41,982 women), including 3,230 with cancer (636 gastric cancer, 598 colorectal cancer, 397 lung cancer, 233 breast cancer, 193 liver cancer, 1,173 other cancers) and 1,386 with CVD (227 myocardial infarction, 1,159 stroke), were included in our analysis.

Person-years of follow-up were calculated for each subject from the starting point to the date of diagnosis, date of emigration from the study area, date of death, or end of the follow-up period (December 31, 2002), whichever occurred first. Subjects lost to follow-up were censored at the last confirmed date of their presence in the study area. A total of 456,084 person-years for the cancer analysis and 459,320 person-years for the CVD analysis were accrued.

Hazard ratios and 95 percent confidence intervals were calculated for the categories of energy-adjusted fruit and vegetable consumption in quartiles for men and women combined, with the lowest consumption category as the reference, by using Cox proportional hazards models and adjusting for potential confounding variables according to the SAS PHREG procedure (SAS Institute, Inc., Cary, North Carolina). A residual model was used for energy adjustment of fruit and vegetable consumption (36).

We conducted the initial analyses by adjusting for gender, age at the starting point (5-year groups), and study area (nine public health center areas). In the multivariate model, we further adjusted for smoking status (never, past, and current), alcohol consumption (none, occasional, 1–149, 150–299, 300–449, and ≥450 g of ethanol/week), body mass index in kg/m2 (<19, 19–22.9, 23–26.9, and ≥27), physical activity in metabolic equivalent task-hours/day (<30, 30–34.9, 35–39.9, and ≥40), quartile of total energy intake, current medication status (hypertension, hyperlipidemia, diabetes mellitus), daily vitamin supplement use, and screening examination (blood pressure, chest radiograph, gastric photofluorography, gastrointestinal endoscopy, fecal occult blood test, barium enema, colonoscopy for men and women, mammography, Papanicolaou smear for women). Information on these covariates was obtained by self-administered questionnaire. Subjects for whom values for any of the potential confounders were missing were excluded from the multivariate analysis (7,230 were excluded, and 70,661 remained in the analyses). We also assessed linear associations by using the median values of fruit and/or vegetable intake for each quartile.

In addition, we performed subgroup analyses according to gender and smoking status ("never" as nonsmoker and "past" and "current smoker" as ever smoker), age (<60 or ≥60 years), cohort (I or II), body mass index (<19 or 19–26.9 or ≥27 kg/m2), and alcohol intake (<150 or ≥150 g ethanol/week). In this paper, all p values are two sided, and statistical significance was determined at the p < 0.05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Total fruit and vegetable intake by the subjects ranged from a median value of 186 g/day in the lowest quartile to 733 g/day in the highest quartile. Subjects whose fruit and vegetable consumption was higher were slightly older.

Table 1 shows gender-specific and age-adjusted values comparing the characteristics of the subjects according to quartiles of total fruit and vegetable consumption. Both men and women whose fruit and vegetable consumption was higher were less likely to be ever smokers or heavy drinkers, and they were more likely to use vitamin supplements and have undergone various screening examinations. Levels of physical activity or prevalence of overweight did not differ with higher fruit and vegetable intake.


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  		TABLE 1. Characteristics of subjects according to quartile of total fruit and vegetable consumption, Japan Public Health Center-based Prospective Study, 1995 and 1998 (n = 77,891)

 
A significant inverse association was found between fruit consumption and risk of CVD, but not between vegetable intake and risk of CVD (table 2). Total fruit and vegetable intake was not significantly associated with CVD risk. The only specific fruit or vegetable item significantly inversely associated with CVD risk was citrus fruits. No significant association was found between risk of total cancer and fruit or vegetable intake, whether combined or separated. No specific fruit or vegetable was significantly associated with risk of total cancer.


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  		TABLE 2. Hazard ratios and 95% confidence intervals for cardiovascular disease and cancer according to quartile of fruit and vegetable consumption, Japan Public Health Center-based Prospective Study, 1995 and 1998–2002 (n = 77,891)

 
A stratified analysis according to gender showed a significant inverse trend between fruit consumption and risk of CVD among women only (table 3). No associations were found between fruit or vegetable consumption and cancer for either gender. A stratified analysis according to smoking status showed no association between fruit or vegetable intake and CVD risk among ever smokers, but a significant inverse association was found between fruit consumption (not for vegetables) and CVD risk among nonsmokers. These findings remained unchanged when the stratified analyses were limited to men: multivariate hazard ratios for the highest quartile of fruit intake versus the lowest were 0.87 (95 percent confidence interval (CI): 0.64, 1.19) for male ever smokers (trend p = 0.39) and 0.74 (95 percent CI: 0.45, 1.20) for male never smokers (trend p = 0.13). No association was found between fruit or vegetable consumption and cancer risk for ever smokers or nonsmokers. Stratified analyses by cohort (cohort I or II), body mass index (<19 or 19–26.9 or ≥27 kg/m2), age (<60 or ≥60 years), and alcohol intake (<150 or ≥150 g ethanol/week) showed similar results—that higher fruit consumption was associated with lower risk of CVD but that neither fruit nor vegetable consumption was associated with cancer risk (data not shown).


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  		TABLE 3. Hazard ratios and 95% confidence intervals for cancer and cardiovascular disease according to quartile of fruit and vegetable consumption by gender and smoking status, Japan Public Health Center-based Prospective Study, 1995 and 1998–2002 (n = 77,891)

 
To sort out the influences of gender and smoking on the association between fruit intake and CVD, we assessed the age-adjusted incidence of CVD according to quartiles of fruit consumption by gender and smoking status (figure 1). For both men and women, CVD incidence was lower in nonsmokers than ever smokers, and the inverse association between fruit intake and risk was more remarkable among nonsmokers than ever smokers. In contrast, for both ever smokers and nonsmokers, CVD incidence was basically comparable between men and women, and the dose-response association between fruit intake and risk was comparable between men and women. The results therefore suggest that the apparent gender differences in the association between fruit intake and CVD are attributable in large part to the differences in the association by smoking status and the higher prevalence of ever smokers among men (65.3 percent) than among women (6.3 percent).


Figure 1
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  		FIGURE 1. Age-adjusted cardiovascular disease (CVD) incidence according to quartile of fruit consumption, by gender and smoking status, Japan Public Health Center-based Prospective Study, 1995 and 1998–2002 (n = 77,891).

 
Because the distribution of fruit and vegetable consumption differed by gender, we performed a separate analysis according to gender-specific quartiles of fruit and vegetable consumption. The results were similar to those obtained with gender-combined quartiles. Specifically, CVD risk for women was significantly inversely associated with total fruit and vegetable consumption (multivariate hazard ratio (HR) of highest quartiles versus the lowest = 0.73, 95 percent CI: 0.56, 0.95; trend p = 0.02) and with fruit consumption (HR = 0.78, 95 percent CI: 0.60, 1.01; trend p = 0.06), and we found a nonsignificant, but inverse association with vegetable consumption (HR = 0.81, 95 percent CI: 0.63, 1.05; trend p = 0.14). No association between fruit or vegetable consumption and risk of CVD was found for men. No significant association was found between fruit or vegetable intake and cancer risk for women (multivariate HR for highest quartiles of total fruit and vegetable consumption versus the lowest = 1.04, 95 percent CI: 0.88, 1.23; trend p = 0.77) or men (HR = 0.90, 95 percent CI: 0.78, 1.04; trend p = 0.22). Citrus fruits was the only specific food group significantly inversely associated with CVD risk for both men (HR = 0.76, 95 percent CI: 0.61, 0.94; trend p = 0.03) and women (HR = 0.77, 95 percent CI: 0.59, 1.00; trend p = 0.06). No other individual food groups were associated with risk of cancer for men or women (data not shown).

The results were not materially different in the analyses that excluded the subjects who reported medication use for hypertension, hyperlipidemia, or diabetes mellitus or that excluded cases of cancer or CVD diagnosed during the first 2 years of follow-up (data not shown). The results did not differ materially in the analyses using a continuous variable for number of cigarettes smoked per day to reduce the potential for residual confounding by smoking. In addition, these results did not change substantially in the analyses in which deciles of fruit or vegetable consumption were used: the multivariate hazard ratios for the highest versus the lowest decile of consumption were 0.81 (95 percent CI: 0.61, 1.08) for fruit and CVD (trend p = 0.01), 0.87 (95 percent CI: 0.68, 1.13) for vegetables and CVD (trend p = 0.44), 1.07 (95 percent CI: 0.89, 1.27) for fruit and cancer (trend p = 0.57), and 1.02 (95 percent CI: 0.85, 1.21) for vegetables and cancer (trend p = 0.32).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
This population-based prospective cohort study in Japan revealed a significant inverse association between fruit consumption and risk of CVD, but no significant association between fruit or vegetable consumption and risk of total cancer. The inverse association between fruit and CVD was more apparent among women and nonsmokers than among men and smokers. To our knowledge, this is the first prospective cohort study to examine associations between fruit and vegetable consumption and risk of cancer and CVD simultaneously in an Asian population.

Previous studies that examined associations between fruit and vegetable consumption and risk of total cancer and CVD simultaneously in Western populations found inverse associations that were more consistent for CVD than for total cancer (21–26): five studies found significant protective associations between consumption of fruit (21–23), vegetables (22), or fruit and vegetables combined (21, 25, 26) and risk of CVD, but only three studies showed significant inverse associations between consumption of vegetables (22) or fruit and vegetables combined (24, 26) and risk of total cancer. However, all of those studies except one (21) had methodological limitations. Five studies included fewer than 10,000 subjects, resulting in a small number of cases (22–26); three studies used a FFQ that contained fewer than four items for fruit and vegetables (22, 23, 25); and three studies used mortality endpoints alone (24–26). The two studies that found inverse associations for both cancer and CVD used a small number of subjects (n = 3,389) (22) or mortality endpoints (26). The only study with none of these limitations yielded findings consistent with our own—that consumption of fruit and vegetables was inversely associated with the risk of CVD but not with the risk of total cancer (21).

In this study, the variations among subjects regarding fruit and vegetable consumption were sufficiently large; median intake in the highest quartile group (733 g) was fourfold that in the lowest quartile group (186 g) (table 1) and greater than in a study based on the 4-day dietary records that found inverse associations between fruit and vegetable intake and cancer as well as CVD (a threefold difference between the highest and lowest quintiles) (26). The use of a general population and a FFQ with a large number of fruit and vegetable items (n = 46) contributed to the large variations. This strength would also argue against the possibility that the observed absence of any association with cancer incidence is attributable to insufficient variation in fruit and vegetable consumption.

The subgroup analyses showed clearer inverse associations between fruit intake and CVD risk among women and nonsmokers than among men and smokers. Oxidative stress caused by smoking may increase consumption of the body's store of antioxidants and dietary requirements for the nutrients. The increased requirement for antioxidants among smokers may offset the protective effect of fruit and vegetables against CVD (37–41). The differences in results according to gender would in part reflect the difference in prevalence of ever smokers between men and women.

Our study has several potential limitations. First, the validity of the FFQ for fruit and vegetable intake was moderate at best (r = 0.34–0.57). Although it is not certain whether measurement error in the FFQ resulted in biased associations toward or away from the null, it would be reasonable to assume that this bias operates in the same directions for CVD and cancer. Under this assumption, if, for instance, measurement error in the FFQ resulted in biased association between fruit and CVD toward the null, then the observed associations would have underestimated the true magnitude of the protective association between fruit and CVD as well as cancer. Alternatively, if measurement error in the FFQ resulted in biased associations between fruit and CVD away from the null, then the observed associations would have overestimated the no or small protective association between fruit and CVD while underestimating the risk-increasing association between fruit and cancer. The former scenario would be more plausible than the latter.

Second, stroke accounted for most (84 percent) of the CVD, thereby limiting comparability of the findings in this study and previous studies in Western populations, in which coronary heart disease accounted for the majority of CVD. This may also account in part for the observed inverse association with fruit intake and absence of association with vegetable intake, since a meta-analysis of cohort studies on fruit, vegetables, and stroke showed a clearer inverse association for fruit than for vegetables (42). Third, although we measured and adjusted for possible confounding variables as much as possible, effects of confounding by unmeasured variables cannot be totally discarded.

In conclusion, the results of this population-based prospective cohort study in Japan suggest a protective association between fruit consumption and risk of CVD and no association between fruit or vegetable consumption and risk of total cancer.


   ACKNOWLEDGMENTS
 
This study was supported by Grants in Aid for Cancer Research and for the Third-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan.

Members of the Japan Public Health Center-based Prospective Study Group (principal investigator: S. Tsugane): S. Tsugane, M. Inoue, T. Sobue, and T. Hanaoka, Research Center for Cancer Prevention and Screening, National Cancer Center; J. Ogata, S. Baba, T. Mannami, and A. Okayama, National Cardiovascular Center; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, and I. Hashimoto, Iwate Prefectural Ninohe Public Health Center (PHC); Y. Miyajima, N. Suzuki, S. Nagasawa, and Y. Furusugi, Akita Prefectural Yokote PHC; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, and Y. Miyagawa, Nagano Prefectural Saku PHC; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, and H. Sakiyama, Okinawa Prefectural Chubu PHC; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, and F. Shoji, Katsushika PHC; A. Murata, K. Minato, K. Motegi, and T. Fujieda, Ibaraki Prefectural Mito PHC; K. Matsui, T. Abe, M. Katagiri, and M. Suzuki, Niigata Prefectural Kashiwazaki and Nagaoka PHC; M. Doi, A. Terao, and Y. Ishikawa, Kochi Prefectural Chuo-higashi PHC; H. Sueta, H. Doi, M. Urata, N. Okamoto, and F. Ide, Nagasaki Prefectural Kamigoto PHC; H. Sakiyama, N. Onga, and H. Takaesu, Okinawa Prefectural Miyako PHC; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, and M. Ichii, Osaka Prefectural Suita PHC; S. Matsushima and S. Natsukawa, Saku General Hospital; M. Akabane, Tokyo University of Agriculture; M. Konishi and K. Okada, Ehime University; H. Iso, Osaka University; Y. Honda and K. Yamagishi, Tsukuba University; H. Sugimura, Hamamatsu University; Y. Tsubono, Tohoku University; M. Kabuto, National Institute for Environmental Studies; S. Tominaga, Aichi Cancer Center Research Institute; M. Iida and W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease; S. Sato, Osaka Medical Center for Health Science and Promotion; N. Yasuda, Kochi University; S. Kono, Kyushu University; K. Suzuki, Research Institute for Brain and Blood Vessels Akita; Y. Takashima, Kyorin University; E. Maruyama, Kobe University; the late M. Yamaguchi, Y. Matsumura, S. Sasaki, and S. Watanabe, National Institute of Health and Nutrition; T. Kadowaki, Tokyo University; Y. Kawaguchi, Tokyo Medical and Dental University; and H. Shimizu, Sakihae Institute.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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