Published online before print May 26, 2005, doi: 10.1161/01.STR.0000169925.57251.4e
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(Stroke. 2005;36:1377.)
© 2005 American Heart Association, Inc.
Original Contributions |
Body Mass Index and Mortality From Cardiovascular Disease Among Japanese Men and Women
The JACC Study
From the Department of Public Health Medicine, Doctoral program in Social and Environmental Medicine (R.C., H.I.), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; the Department of Public Health/Health Information Dynamics (H.T., T.K.), Fields of Science, Program of Health and Community Medicine, Nagoya University Graduate School of Medicine, Japan; the Department of Food Science and Nutrition (C.D.), School of Human Environmental Science, Mukogawa Women’s University, Hyogo, Japan; Infectious Disease Surveillance Cancer (A.Y.), Infectious Disease Research Division, Hyogo Prefectural Institute of Public Health and Environmental Science, Japan; the Department of Public Health (S.K.), Aichi Medical University, Wakayama, Japan; the Department of Social Medicine and Cultural Sciences (Y. Watanabe), Research Institute for Neurological Diseases and Geriatrics, Kyoto Prefectural University of Medicine, Japan; the Department of Health and Environmental Sciences (A.K.), Graduate School of Medicine, Kyoto University, Japan; the Department of Hygiene (Y. Wada), Hyogo College of Medicine, Japan; Juntendo University School of Medicine (Y.I.), Tokyo, Japan; the Department of Preventive Medicine/Biostatistics and Medical Decision Making (A.T.), Field of Social Science, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Japan.
Reprint requests to Professor Hiroyasu Iso, MD, Department of Public Health Medicine, Doctoral program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tuskuba, Ibaraki 305-8575 Japan. E-mail fvgh5640{at}mb.infoweb.ne.jp
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Abstract |
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Background and Purpose— Although overweight is an important risk factor for cardiovascular disease in Western countries, the impact of overweight has not been well elucidated in Japan, where its prevalence is low.
Methods— A total of 104 928 Japanese (43 889 men and 61 039 women) aged 40 to 79 years, free of stroke, coronary heart disease, and cancer at entry participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) between 1988 and 1990. Systematic surveillance was completed until the end of 1999, with 1 042 835 person years of follow-up, and the underlying causes of death were determined based on the International Classification of Diseases.
Results— There were 765 total strokes (191 intraparenchymal hemorrhages), 379 coronary heart diseases, and 1707 total cardiovascular diseases for men; and for women, there were 685 (145), 256, and 1432, respectively. Compared with persons with body mass index (BMI) 23.0 to 24.9, those with BMI 
27.0 kg/m2 had a higher risk of coronary heart disease; for men and women, the respective multivariate relative risk (95% CI) was 2.05 (1.35 to 3.13) and 1.58 (0.95 to 2.62). Persons with BMI <18.5 kg/m2 had higher risk of total stroke and intraparenchymal hemorrhage, for men and women, the respective multivariate relative risk was 1.29 (1.01 to 1.49) and 1.92 (1.49 to 2.47) for total stroke and 1.96 (1.16 to 3.31) and 2.32 (1.36 to 3.97) for intraparenchymal hemorrhage. These excess risks did not alter materially when deaths within 5 years were excluded or when smoking status was taken into account.
Conclusions— For Japanese men and women, high BMI was associated with increased risk of coronary heart disease, whereas low BMI was associated with intraparenchymal hemorrhage.
Key Words: body mass index • coronary heart disease • follow-up studies • mortality • stroke
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Introduction |
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Obesity is an important risk factor for cardiovascular disease in Western countries.1–3 Persons with body mass index (BMI)
30 kg/m2 had 1.5- to 3-fold higher mortality from cardiovascular disease.3–7 More than 80% of the estimated deaths attributable to obesity occurred among individuals with BMI 30 kg/m2.1 In the United States, the prevalence of BMI 30 kg/m2 increased from 12% in 1991 to 18% among adults 18 years of age in 1998.2 But in Japan, the percentage of those with BMI 30 kg/m2 was only 3.2% in 1998 among adults 15 years of age.8 Low BMI was also associated with increased mortality from total deaths3,5,6,9 and stroke.10–12 However, a previous study showed that the inverse association for hemorrhagic stroke was confined to smokers.4 We examined comprehensively the relationships between BMI and mortality attributable to total stroke, stroke subtypes, coronary heart disease, and total cardiovascular disease among Japanese men and women in a large prospective cohort study.
Subjects and Methods
Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) began in 1988 to 1990, when 110 792 individuals (46 465 men and 64 327 women) aged 40 to 79 years living in 45 communities across Japan participated in municipal health screening examinations and completed self-administered questionnaires about current height and weight, their lifestyles, and medical histories of previous cardiovascular disease and cancer.13 Informed consent was obtained from them when they completed the questionnaire. Follow-up surveys were conducted annually to verify the vital status of the participants. Among them, height and weight data were available for 45 893 men and 63 691 women. BMI was calculated in the formula of weight (kg)/height (m2). Then we excluded 2576 men and 3288 women who had a history of stroke, coronary heart disease, or cancer at baseline. Therefore, 43 889 men and 61 039 women were enrolled in the present study.
For mortality surveillance in each community, investigators conducted systematic review for death certificates, all of which were forwarded to the public health center in the area of residency. Mortality data were sent centrally to the Ministry of Health and Welfare, and the underlying causes of death were coded according to the International Classification of Diseases, 9th Revision, from 1988 to 1994, and the 10th revision from 1995 to 1999 for the National Vital Statistics. Therefore, all deaths that occurred in the cohort were ascertained by death certificates from a public health center, except for subjects who died after they had moved from their original community, in which case subjects was treated as censored cases. The follow-up was conducted until the end of 1999, and the average follow-up for the participants was 9.9 years. The ethics committee of the University of Tsukuba approved the present study.
Statistical analyses were based on sex-specific incidence rates of stroke during the follow-up from between 1988 and 1990 to 1999. For each participant, periods of follow-up were calculated from the date of filling out the baseline questionnaire to his/her death, moving out of the community, or the end of 1999, whichever occurred first. The sex-specific relative risk of mortality from cardiovascular disease was defined as the death rate among participants in 6 categories of BMI (<18.5, 18.5 to 20.9, 21.0 to 22.9, 23.0 to 24.9, 25.0 to 26.9, and 27.0 kg/m2). Because of the relatively low percentage of the categories of persons with BMI 30.0 kg/m2, the categories of BMI 27.0 to 29.9 and 30.0 kg/m2 were combined. We used categories of BMI 23.0 to 24.9 kg/m2 as the reference because of the lowest age-adjusted mortality in both sexes.
Sex-specific age-adjusted means and proportions of selected cardiovascular risk factors and psychological factors were presented among the categories of BMI using analysis of covariance or 
2 tests. Test for a linear trend across the BMI categories was conducted by linear regression or logistic regression model, adjusting for age using a median variable of BMI in each BMI category. The age-adjusted and multivariate-adjusted relative risks and their 95% CIs were calculated after adjustment for age and potential confounding factors by using the Cox proportional hazards model.
The confounding variables included smoking status (never-smoker; ex-smoker; and current smoker, 1 to 19, and 20 cigarettes per day), alcohol intake category (never-drinker; ex-drinker; and current drinker, ethanol 1 to 22, 23 to 45, 46 to 68, and 69 g per day), hours of walking (seldom, <30, 30 to 59, and 60 minutes per day), hours of sleep (<6.0, 6.0 to 6.9, 7.0 to 7.9, 8.0 to 8.9, and 9.0 hours per day), college or higher education (primary school, junior high school, high school, college or more), high perceived mental stress (low, medium, high), frequency of fish intake (never, 1, 1 to 2, 3 to 4, and 5 servings per week), hypertension (no, yes), and history of diabetes (no, yes). Hypertension was defined as 140 mm Hg of reported systolic blood pressure, 90 mm Hg of reported diastolic blood pressure, or antihypertensive medication use. The analysis was repeated by exclusion of death within 5 years of the follow-up and stratified by smoking status (never-smokers versus ex-smokers and current smokers). The significance of the interaction of smoking status with BMI was tested using an interaction term of continuous 2 variables in multivariate models.
Cause-specific mortality was determined by total cardiovascular disease (International Classification of Disease, 9th Revision codes 390 to 459, 10th revision, codes I01 to I99), total coronary heart disease (codes 410 to 414 and I20 to I25), and total stroke (430 to 438 and I60 to I69), separately. Further groupings of total strokes were also conducted as intraparenchymal hemorrhage (431 and I61), subarachnoid hemorrhage (430 and I60), and ischemic stroke (433 to 434 and I63).
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Results |
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During the 9.9-year follow-up of 43 889 men and 61 039 women aged 40 to 79 years, 1 707 men and 1 432 women died from total cardiovascular disease. These deaths among men included 765 total strokes (191 intraparenchymal hemorrhages and 300 ischemic strokes) and 397 coronary heart diseases. The respective number of deaths among women was 685 (145 and 240) and 256. The percent distributions of BMI was 10.4% for <18.5, 22.2% for 18.5 to 20.9, 27.1% for 21.0 to 22.9, 22.9% for 23.0 to 24.9, 11.4% for 25.0 to 26.9, and 6.0% for
27.0 kg/m2 among men. And percent distributions for women were 12.2%, 19.7%, 25.2%, 21.7%, 12.4%, and 8.8%, respectively. The mean BMI was 22.6 in men and 22.9 in women.
Table 1 shows sex-specific selected cardiovascular risk factors by 6 categories of BMI. For men and women, persons with BMI 27.0 kg/m2 were more hypertensive, more diabetic, drunk more, and walked less compared with those with lower BMI categories. Men with BMI 27.0 kg/m2 were younger, smoked less, and had higher fish intake, whereas women with BMI 27.0 kg/m2 were less educated compared with those lower BMI categories. Men with BMI <18.5 kg/m2 were less educated and more stressed compared with those higher BMI categories. We had the baseline data of serum total cholesterol for 27.6% of the total subjects. Serum total cholesterols levels were positively correlated with BMI for men and women. The proportion of serum total cholesterol <4.14 mmol/L (160 mg/dL) were 27.1% for BMI of <18.5 kg/m2, declining to 11.5% for BMI of 27.0 kg/m2 in men and 12.1% to 6.7% in women (data not shown).
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Table 2 shows sex-specific age- and multivariate-adjusted relative risks of mortality from cardiovascular disease according to BMI categories. There was a U-shaped relationship between BMI and risk of mortality from total cardiovascular disease, with a nadir at BMI of 23.0 to 24.9 kg/m2 for men and at BMI of 25.0 to 26.9 kg/m2 for women (Figure). Persons with BMI 27.0 kg/m2 had increased risk of mortality from coronary heart disease for men and women, although the trend did not reach statistical significance for women; the multivariate relative risk (95% CI) was 2.05 (1.35 to 3.13) for men and 1.58 (0.95 to 2.62) for women. When early deaths within 5 years were excluded, these relative risks were 1.94 (1.18 to 3.19) and 1.53 (0.88 to 2.67), respectively.
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P<0.01; 
P<0.001.Persons with BMI <18.5 kg/m2 had increased risk of mortality from total stroke, intraparenchymal hemorrhage, and total cardiovascular disease for both sexes; the respective multivariate relative risks were 1.29 (1.01 to 1.49), 1.96 (1.16 to 3.31), and 1.46 (1.24 to 1.72) for men and 1.92 (1.49 to 2.47), 2.32 (1.36 to 3.97), and 1.72 (1.45 to 2.04) for women. When early deaths were excluded, these relative risks were 1.15 (0.85 to 1.57), 2.35 (1.18 to 4.70), and 1.15 (0.93 to 1.42) for men and 1.74 (1.28 to 2.35), 2.25 (1.11 to 4.56), and 1.57 (1.28 to 1.94) for women. Women with BMI <18.5 kg/m2 also had increased risk of mortality from coronary heart disease and ischemic stroke; the respective multivariate relative risks were 1.76 (1.16 to 2.68) and 1.90 (1.22 to 2.96). When early deaths were excluded, these excess risks of mortality were reduced and were no longer statistically significant for coronary heart disease but remained significant for ischemic stroke; the respective multivariate relative risks were 1.42 (0.89 to 2.26) and 1.75 (1.08 to 2.85).
The associations between BMI and mortality were examined when stratified by smoking status (data not shown). The excess risk of mortality from coronary heart disease for BMI 27.0 kg/m2 did not alter significantly according to smoking status. The multivariate relative risks for men were 1.47 (0.44 to 4.90) among never-smokers and 2.42 (1.50 to 3.91) among former and current smokers; the interaction was not statistically significant (P=0.16). The respective multivariate relative risks for women were 1.61 (0.87 to 2.98) and 1.11 (0.24 to 5.14; P for interaction=0.57). Similarly, the excess risks of intraparenchymal hemorrhage for BMI <18.5 kg/m2 did not vary according to smoking status. The multivariate relative risks for men were 1.89 (0.51 to 6.97) among never-smokers and 1.95 (1.07 to 3.55) among former and current smokers; the interaction was not statistically significant (P=0.66). The respective multivariate relative risks for women were 2.04 (1.09 to 3.83) and 8.10 (0.63 to 105; P for interaction=0.96). These results did not alter materially when we categorized the smoking status into current smokers and noncurrent smokers.
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Discussion |
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In the present large prospective study of middle-aged Japanese men and women, we observed that persons with BMI
27.0 kg/m2 had 1.6- to 2.1-fold excess mortality from coronary heart disease, whereas those with BMI <18.5 kg/m2 had 2.0- to 2.3-fold excess mortality from intraparenchymal hemorrhage and 1.3- to 2.0-fold excess mortality from total stroke. There was a U-shaped relationship between BMI and risk of mortality from total cardiovascular disease, which was consistent with the findings from previous studies in the United States.2 These associations did not alter materially when we excluded deaths within 5 years of follow-up or smokers.
The excess risk of mortality from coronary heart disease among persons with BMI 27.0 kg/m2 was consistent with the finding from a previous Japanese study.14 A prospective cohort study6 of >1 million US adults showed that persons with BMI 30.0 kg/m2 had 1.5- to 3-fold higher mortality from total cardiovascular disease compared with those with BMI of 23.5 to 24.9 kg/m2 and >80% of the estimated cardiovascular deaths attributable to individuals with BMI 30 kg/m2.1 We did not examine the effect of BMI 30.0 kg/m2 because only 1.6% of the participants (1.0% men and 2.0% women) had this high BMI category. According to the 1998 National Nutrition Survey of Japan, the prevalence of persons with BMI 30.0 kg/m2 had 2.5% for men and 3.6% for women aged 15 years.8 This prevalence was much lower than that in the United States (17.7% for men and 18.1% for women in 1998).2
The excess risk of intraparenchymal hemorrhage among men with BMI <18.0 kg/m2 has been reported recently in Korean men,11 which was consistent with our results. However, in that study, there was also an excess risk from intraparenchymal hemorrhage among overweight men, showing a U-shaped association with BMI. The Physicians’ Health Study suggested an excess risk of fatal hemorrhagic stroke among US white men with BMI <23.0 kg/m2.12 The Nurses’ Health Study showed that the excess risk of hemorrhagic stroke among US women with BMI <21.0 kg/m2 was confined to smokers.4 However, our study showed that the excess risk of mortality from intraparenchymal hemorrhage was similarly observed for smokers and nonsmokers. The excess risk of hemorrhagic stroke among Asians with BMI <18.0 to 18.5 kg/m2 and among Americans with BMI <21.0 to 23.0 kg/m2 suggests that low BMI, the cut points of which are different among ethnicities, may be a marker for increased risk of hemorrhagic stroke and not so much causally associated.
Associations between low serum total cholesterol and risk of intraparenchymal hemorrhage in previous prospective studies15,16 and a positive correlation between cholesterol and BMI in the present study suggest low cholesterol as part of a potential causal pathway between low BMI and intraparenchymal hemorrhage. It is also possible that low cholesterol may be a marker for something else that increased the risk of intraparenchymal hemorrhage.
The present study has several limitations. We used self-reported weight and height at enrollment to calculate BMI, in which measurement error may exist: an underestimation of weight and an overestimation of height.17 However, a previous study of 1823 men and women aged 40 to 68 years showed that BMI estimated from self-reporting was highly correlated with actual BMI (r=0.94), and their mean difference was small (mean±SD=23.3±3.0 versus 23.2±2.9).18 Second, we used the mortality data, not incident data, as end points, which may lead to misclassification in the diagnosis of stroke subtypes in particular. However, a widespread use of computed tomography scans in Japanese local hospitals since the 1980s has probably made a death certificate diagnosis of stroke subtypes sufficiently accurate.19
In conclusion, high BMI was associated with increased risk of mortality from coronary heart disease, whereas low BMI was associated with intraparenchymal hemorrhage, showing a U-shaped relationship between BMI and total cardiovascular disease for Japanese men and women.
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Acknowledgments |
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This work was supported by a grant-in-aid for scientific research on priority areas (C; 2; No. 12218216) from the Ministry of Education, Science, Sports, and Culture of Japan. The authors express their sincere appreciation to Dr Kunio Aoki, Professor Emeritus, Nagoya University School of Medicine and the former chairman of the JACC Study Group, and also to Dr Haruo Sugano, the former director of the Cancer Institute of the Japanese Foundation for Cancer Research, who greatly contributed to the initiation of the study. The present investigators involved, with the coauthorship of this article, in the JACC Study and their affiliations are as follows: Dr Akiko Tamakoshi (present chairman of the study group), Nagoya University Graduate School of Medicine; the Dr Mitsuru Mori, Sapporo Medical University School of Medicine; Dr Yutaka Motohashi, Akita University School of Medicine; Dr Ichiro Tsuji, Tohoku University Graduate School of Medicine; Dr Yosikazu Nakamura, Jichi Medical School; Dr Hiroyasu Iso, Institute of Community Medicine, University of Tsukuba; Dr Haruo Mikami, Chiba Cancer Center; Dr Yutaka Inaba, Juntendo University School of Medicine; Dr Yoshiharu Hoshiyama, Showa University School of Medicine; Dr Hiroshi Suzuki, Niigata University School of Medicine; Dr Hiroyuki Shimizu, Gifu University School of Medicine; Dr Kenji Wakai, Aichi Cancer Center Research Institute; Dr Hideaki Toyoshima, Nagoya University Graduate School of Medicine; Dr Shinkan Tokudome, Nagoya City University Graduate School of Medicine; Dr Yoshinori Ito, Fujita Health University School of Health Sciences; Dr Shuji Hashimoto, Fujita Health University School of Medicine; Dr Shogo Kikuchi, Aichi Medical University School of Medicine; Dr Akio Koizumi, Graduate School of Medicine and Faculty of Medicine, Kyoto University; Dr Takashi Kawamura, Kyoto University Center for Student Health; Dr Yoshiyuki Watanabe, Kyoto Prefectural University of Medicine, Research Institute for Neurological Diseases and Geriatrics; Dr Tsuneharu Miki, Kyoto Prefectural University of Medicine; Dr Chigusa Date, Faculty of Human Environmental Sciences, Mukogawa Women’s University; Dr Kiyomi Sakata, Wakayama Medical University; Dr Takayuki Nose, Tottori University Faculty of Medicine; Dr Norihiko Hayakawa, Research Institute for Radiation Biology and Medicine, Hiroshima University; Dr Takesumi Yoshimura, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan; Dr Akira Shibata, Kurume University School of Medicine; Dr Naoyuki Okamoto, Kanagawa Cancer Center; Dr Hideo Shio, Shiga Medical Center; Dr Yoshiyuki Ohno, Nagoya University Graduate School of Medicine; Dr Tomoyuki Kitagawa, Cancer Institute of the Japanese Foundation for Cancer Research; Dr Toshio Kuroki, Gifu University; and Dr Kazuo Tajima, Aichi Cancer Center Research Institute. The past investigators of the study group are listed in the references section13 except for the following 2 members (affiliations are of those who participated in the study): Dr Takashi Shimamoto, Institute of Community Medicine, University of Tsukuba; and Dr Heizo Tanaka, Medical Research Institute, Tokyo Medical and Dental University.
Received May 6, 2004; revision received August 25, 2004; accepted August 31, 2004.
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