Serum Triglycerides and Risk of Coronary Heart Disease among Japanese Men and Women
Hiroyasu Iso1,
Yoshihiko Naito2,
Shinichi Sato2,
Akihiko Kitamura2,
Tomonori Okamura2,
Tomoko Sankai1,
Takashi Shimamoto1,
Minoru Iida2 and
Yoshio Komachi3
1 Institute of Community Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki-ken, Japan.
2 Department of Epidemiology and Mass Examination for Cardiovascular Diseases, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi, Higashinari-ku, Osaka, Japan.
3 Osaka Prefectural Institute of Public Health, 1-3-69 Nakamichi, Higashinari-ku, Osaka, Japan.
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ABSTRACT
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To examine the relation of triglycerides with coronary heart disease among populations with low mean total cholesterol, the authors conducted a 15.5-year prospective study ending in 1997 of 11,068 Japanese aged 4069 years (4,452 men and 6,616 women with mean total cholesterol = 4.73 mmol/liter and 5.03 mmol/liter, respectively), initially free of coronary heart disease or stroke. There were 236 coronary heart disease events comprising 133 myocardial infarctions, 68 angina pectoris events, and 44 sudden cardiac deaths. The coronary heart disease incidence was greater in a dose-response manner across increasing quartiles of nonfasting triglycerides for both sexes. The multivariate relative risk of coronary heart disease adjusting for coronary risk factors and time since last meal associated with a 1-mmol/liter increase in triglycerides was 1.29 (95% confidence interval (CI): 1.09, 1.53; p = 0.004) for men and 1.42 (95% CI: 1.15, 1.75; p = 0.001) for women. The trend was similar for myocardial infarction, angina pectoris, and sudden cardiac death. The relation of triglycerides with coronary heart disease was not influenced materially by total cholesterol levels or, in a subsample analysis (51% of total sample), by high density lipoprotein cholesterol levels. Nonfasting serum triglycerides predict the incidence of coronary heart disease among Japanese men and women who possess low mean values of total cholesterol. Further adjustment for high density lipoprotein cholesterol suggests an independent role of triglycerides on the coronary heart disease risk.
cholesterol; coronary disease; incidence; triglycerides
Abbreviations:
CI, confidence interval; HDL, high density lipoprotein; LDL, low density lipoprotein; SD, standard deviation.
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INTRODUCTION
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Contributions of high total cholesterol, high low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol concentrations to the development of coronary heart disease are well established (1
, 2
), but the role of triglycerides is controversial (3
). Accumulated biologic evidence relating to triglycerides, atherosclerosis, and thrombosis has indicated the potential importance of triglycerides in the etiology of coronary heart disease (3
). Prospective studies generally have shown a univariate positive relation between serum triglyceride concentrations and the risk of coronary heart disease (4






















28
). In some studies (4







13
), but not all (14












28
), the relation was no longer statistically significant after controlling for total, LDL, or HDL cholesterol using multivariate regression analyses. A recent meta-analysis of 17 prospective studies showed that adjustment for HDL cholesterol attenuated the relation between triglycerides and the risk, but the pooled relative risk estimates were statistically significant for both men and women (29
). Such statistical analyses, however, are likely to underestimate the independent role of triglycerides in the development of coronary heart disease because of the large within-person variability of triglyceride levels (30
) and the interrelation of triglycerides with total, LDL, and HDL cholesterol in lipid metabolism (31
).
To partially solve this methodological problem in epidemiologic studies, several prospective studies have conducted subgroup analyses stratifying on levels of total, LDL, or HDL cholesterol. However, the results have been inconsistent. Two studies of Caucasian men in Europe (8
) and the Unites States (10
) found a significant association between triglycerides and coronary heart disease in the subgroup with lower total or LDL cholesterol but not in the higher total or LDL cholesterol subgroup. The two other studies of European men (11
) and US male physicians (27
) showed that the positive association of triglycerides with coronary heart disease was more pronounced among those with a high LDL cholesterol level or LDL cholesterol/HDL cholesterol ratio. A recent study of European men showed a similar positive association of triglycerides with coronary heart disease risk in each HDL cholesterol tertile (28
). A study of populations with low cholesterol levels, such as Japanese men and women living in Japan, may be valuable to examine the relation between triglycerides and risk of coronary heart disease.
Our a priori hypothesis was that serum triglycerides would be positively associated with the risk of coronary heart disease. Furthermore, the association would be similar in subgroups divided by medians of total and HDL cholesterol levels. To examine these hypotheses, we used the data from a prospective study of 11,068 persons (4,452 men and 6,616 women) over 15.5 years in four Japanese populations in which the mean total cholesterol level was 4.73 mmol/liter for men and 5.03 mmol/liter for women.
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MATERIALS AND METHODS
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Populations
The surveyed population was residents aged 4069 years in four communities who participated in cardiovascular risk surveys between 1975 and 1980 in a northeast rural community, Ikawa, and in a southwest rural community, Noichi, and between 1981 and 1986 in a central rural community, Kyowa, and between 1975 and 1984 in a southwest urban suburb, Yao. The overall participation rate at baseline was 67 percent. Persons with a history of coronary heart disease (n = 61) and persons with missing values of triglycerides (n = 241) were excluded, and the data of 11,068 persons (4,452 men and 6,616 women) were used for the analyses. Subjects were followed up to determine coronary heart disease endpoints occurring by the end of 1997. Persons who moved out of the communities during the follow-up numbered 618 (6 percent), and 1,852 persons died (17 percent). These were censored at the date of moving out or the date of death. The average follow-up was 15.5 years.
There was no significant difference in mean serum triglycerides and means or prevalence of most of the other coronary risk factors at baseline between persons who were contacted during the follow-up (n = 10,422) and those who moved out of the communities (n = 646). The exceptions were 0.24 mmol/liter and 0.06 mmol/liter higher total cholesterol for men and women, respectively; 2.2 g/day higher ethanol intake; and a 5 percent higher smoking rate for women among those followed up than among those lost to follow-up. Therefore, the potential bias by censoring the follow-up for those 646 persons may be small.
Endpoint determination
The coronary heart disease endpoint was ascertained via six sources (32
): 1) national insurance claims, 2) reports by local physicians, 3) ambulance records, 4) death certificates, 5) reports by public health nurses and health volunteers, and 6) cardiovascular risk surveys. From death certificates, cases with certain underlying causes of death (International Classification of Diseases, Ninth Revision, codes 410414, 428, and 429) were selected. To confirm the diagnosis, all living patients were visited or invited to risk factor surveys. Study physicians obtained a medical history and records of electrocardiograms and cardiac enzymes. For deaths, histories were obtained from families, and medical records were reviewed.
The criteria for coronary heart disease were modified from those of a World Health Organization Expert Committee (33
). Painless types of coronary heart disease were not investigated because of difficulty with complete ascertainment. Definite myocardial infarction was indicated by typical chest pain (lasting for 30 minutes or longer) with the appearance of abnormal and persistent Q or QS waves, changes in cardiac enzyme activity, or both. Probable myocardial infarction was indicated by typical chest pain in which the findings of electrocardiogram or enzyme activity were not available. Angina pectoris was defined as repeated episodes of chest pain during effort, especially when walking, usually disappearing rapidly after the cessation of effort or by use of sublingual nitroglycerin. Sudden cardiac death was defined as death within 1 hour of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by more than 1 hour of symptoms that precipitated the terminal event. The symptoms were unassociated with a previous diagnosis of coronary heart disease, stroke, or other identified causes of death. Final diagnoses were made by a panel of three or four study physician-epidemiologists, blinded to the baseline examination data. Definite myocardial infarction and probable myocardial infarction were combined and presented as myocardial infarction, because the relations with serum triglycerides were similar between these two endpoints.
Baseline examination
At baseline, blood was drawn from seated participants into a plain, siliconized glass tube, and the serum was separated. Fasting was not required. The distribution of time since the last meal was 39 percent for <2 hours, 43 percent for 2 hours, 9 percent for 37 hours, and 9 percent for 8 hours and over. Serum triglycerides were measured by an enzymatic method and serum total cholesterol by the Liebermann-Burchard direct method using the Autoanalyzer II (Technicon Instruments, Tarrytown, New York) at the Osaka Medical Center for Cancer and Cardiovascular Diseases (34
). For 51 percent of the total sample (n = 5,641), HDL cholesterol was measured after heparin-manganese precipitation using the Libermann-Burchard method in the same laboratory. Most missing HDL cholesterol values were from the participants in a central rural community in which HDL cholesterol was not measured routinely in 19811986. The Osaka laboratory has been standardized by the Lipid Standardization Program, Centers for Disease Control, Atlanta, Georgia, and successfully met the criteria for precision and accuracy of triglycerides and cholesterol measurements (35
). Serum glucose was measured by the cupric-neocuproine method (36
).
Baseline blood pressures were measured by trained observers using standard mercury sphygmomanometers on the right arm of seated participants after a 5-minute rest (37
). Hypertension was defined as a systolic blood pressure of
160 mmHg and/or diastolic blood pressure of
95 mmHg and/or taking antihypertensive medication, while normotension was defined as systolic blood pressure of <140 mmHg and diastolic blood pressure of <90 mmHg and not taking antihypertensive medication. All others were classified as having borderline hypertension. Height in stocking feet and weight in light clothing were measured. The body mass index was calculated as weight (kg) divided by the square of height (m2). An interview was conducted to ascertain the number of cigarettes smoked per day, usual weekly intake of ethanol in units of go (a Japanese traditional unit of volume corresponding to 23 g of ethanol), menopausal status for women, and serum glucose category (normal, impaired glucose tolerance, and diabetes). Impaired glucose tolerance was defined as a fasting glucose of 6.16.9 mmol/liter and/or a nonfasting glucose of 7.811.0 mmol/liter, without medication use for diabetes. Diabetes was defined as a fasting glucose of 7.0 mmol/liter or more, a nonfasting glucose of 11.1 mmol/liter or more, and/or use of medication for diabetes.
Statistical analysis
Because some previous studies reported that the relation between serum triglycerides and coronary heart disease varied by sex (18
, 19
), sex-specific analyses were conducted as well as sex-adjusted analyses. Age-adjusted mean values and prevalences of covariates were calculated for cases and noncases, and the differences were tested by analysis of covariance or chi-square tests.
Person-years were calculated as the sum of individual follow-up time until the occurrence of incident coronary heart disease, death, emigration, or the end of 1997. The relative risk of coronary heart disease incidence and its 95 percent confidence interval were calculated with reference to the risk of persons with the lowest quartile of serum triglycerides, using the Cox proportional hazards model. A test for trend between serum triglycerides and coronary heart disease was also conducted after log transformation of triglyceride levels. Covariates included age (years), sex, quartiles of serum total cholesterol (mmol liter), and body mass index (kg/m2), smoking status (never, former, and current smokers), hypertensive status (normotension, borderline hypertension, and hypretension), alcohol intake (never, former, and current: <46, 4668, and
69 g/day of ethanol), serum glucose category (normal, impaired glucose tolerance, and diabetes), time since last meal (<2, 2, 37, and
8 hours) and, for women, menopausal status (pre- and postmenopause). The model with a continuous serum glucose value instead of serum glucose category was also examined. Further adjustment for HDL cholesterol (mmol/liter) was conducted among a subsample (n = 5,641, 51 percent of total sample) for whom the data on HDL cholesterol were available. The multivariate-adjusted association between serum triglycerides and coronary heart disease risk was examined while stratified by the medians of serum total and HDL cholesterol levels. The significance of the interaction of total or HDL cholesterol with triglycerides was tested using an interaction term of continuous two-lipid variables in multivariate models.
In this cohort, only 19 percent of the total mortality was related to coronary heart disease. Thus, we also examined the relation between serum triglycerides and total mortality to see the impact of high triglyceride levels on general health among Japanese. Because the relations of serum triglycerides with the incidence of coronary heart disease and total mortality were similar among the five populations sampled, we presented results for the combined cohort.
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RESULTS
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Mean values of selected cardiovascular risk characteristics among men were 138 (standard deviation (SD), 21) mmHg for systolic and 83 (SD, 12) mmHg for diastolic blood pressures, 4.73 (SD, 0.88) mmol/liter for serum total cholesterol, and 1.65 (SD, 1.14) mmol/liter for serum triglycerides. The respective values for women were 134 (SD, 20) mmHg, 80 (SD, 11) mmHg, 5.03 (SD, 0.91) mmol/liter, and 1.54 (SD, 0.93) mmol/liter. Serum HDL cholesterol levels in 51 percent of the total sample were 1.47 (SD, 0.40) mmol/liter for men and 1.48 (SD, 0.34) mmol/liter for women.
During the 15.5-year follow-up, there were 236 coronary heart disease events (135 in men and 101 in women), comprising 133 myocardial infarctions (86 in men and 47 in women), 68 events of angina pectoris (35 in men and 33 in women), and 44 sudden cardiac deaths (19 in men and 25 in women). Seven cases had the occurrence of both angina pectoris and myocardial infarction.
Sex-specific distributions of serum triglyceride concentrations are shown in figure 1. The distributions were skewed to the right, with cases shifted to higher values across the distribution for both men and women. When stratified by time since last meal, there were consistent case-control differences in median triglyceride levels for both men and women (figure 2).

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FIGURE 1. Sex-specific distributions of baseline triglyceride levels among incident cases of coronary heart disease and noncases in a 15.5-year prospective study of 11,068 Japanese ending in 1997.
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FIGURE 2. Sex-specific baseline median triglyceride levels according to time since last meal among incident cases of coronary heart disease and noncases in a 15.5-year prospective study of 11,068 Japanese ending in 1997. The numbers over bars indicate the number of subjects.
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Table 1 compares age-adjusted values of serum triglycerides and selected coronary risk factors at baseline between cases and noncases. Cases had a significantly higher level of serum triglycerides than did noncases for both sexes. As expected, cases had significantly higher levels of blood pressure and serum total cholesterol for both men and women and lower levels of HDL cholesterol only for men. The proportion of nonfasting participants, current smokers, and diabetes and the mean levels of body mass index and ethanol intake did not differ significantly between cases and noncases.
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TABLE 1. Age-adjusted mean values or prevalence of risk factors at baseline for coronary heart disease incident cases and noncases in a 15.5-year prospective study of 11,068 Japanese ending in 1997
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Table 2 presents multivariate-adjusted relative risks of coronary heart disease according to serum triglyceride levels. There was a dose-response relation between serum triglycerides and the risk of coronary heart disease; that is, the multivariate relative risk in the highest versus lowest quartiles of triglycerides was 2.81 (95 percent confidence interval (CI): 1.56, 5.05; p < 0.001) for men and 2.76 (95 percent CI: 1.34, 5.68; p = 0.006) for women. The respective multivariate relative risk associated with a 1-mmol/liter increase in triglycerides was 1.29 (95 percent CI: 1.09, 1.53; p = 0.004) and 1.42 (95 percent CI: 1.15, 1.75; p = 0.001). When a continuous serum glucose value instead of serum glucose category was put into the model, these relative risks did not change materially. To be specific, the multivariate relative risk in the highest versus lowest quartiles of triglycerides was 2.69 (95 percent CI: 1.50, 4.80; p < 0.001) for men and 2.68 (95 percent CI: 1.30, 5.50; p = 0.008) for women; the respective relative risk associated with a 1-mmol/liter increase in triglycerides was 1.28 (95 percent CI: 1.08, 1.52; p = 0.005) and 1.40 (95 percent CI: 1.14, 1.73; p = 0.002) (data not shown in table). The positive relation with serum triglycerides was similarly observed for myocardial infarction, angina pectoris, and sudden cardiac death although the sex-specific relation was not consistently significant for angina pectoris or sudden cardiac death in part because of the small number of cases. Thus, the consistency of results across coronary heart disease endpoints supports their combination in subsequent analyses stratified by total and HDL cholesterol levels.
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TABLE 2. Multivariate relative risks (RRs) and confidence intervals (CIs) of coronary heart disease, myocardial infarction, angina pectoris, and sudden cardiac death according to quartile of triglycerides (TGs) in a 15.5-year prospective study of 11,068 Japanese ending in 1997
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The relation between triglycerides and coronary heart disease was similarly observed for persons with total cholesterol levels lower versus higher than the median for men and women combined, and the interaction term was not statistically significant (table 3). However, for men the relation was more evident for the subgroup with lower total cholesterol levels than that with higher levels, and the interaction was of borderline significance (p = 0.08). Such a potential interaction was not observed for women (p = 0.79).
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TABLE 3. Serum triglycerides and risk of coronary heart disease, stratified by total cholesterol (TC), in a 15.5-year prospective study of 11,068 Japanese ending in 1997
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We conducted a subanalysis with further adjustment for HDL cholesterol (sample n = 5,641). For men and women combined, the multivariate relative risk of coronary heart disease remained significant, with some attenuation of the association (table 4). When examined by sex, the multivariate relative risk was of borderline significance for men (p = 0.09) and remained significant for women (p = 0.04). When stratified by HDL cholesterol levels above versus below the median, we found a similar relation between triglycerides and the risk of coronary heart disease. The interaction term between HDL cholesterol and triglycerides was not statistically significant for men and women combined or for either sex.
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TABLE 4. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) of coronary heart disease according to quartile (Q) of triglyceride in the subsample with high density lipoprotein (HDL) cholesterol in a 15.5-year prospective study of 11,068 Japanese ending in 1997
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There was a positive relation between serum triglycerides and total mortality (not shown in the table). The multivariate relative risk in the highest versus lowest quartiles of triglycerides was 1.29 (95 percent CI: 1.05, 1.58; p = 0.01) for men and 1.20 (95 percent CI: 0.95, 1.51; p = 0.13) for women. The respective multivariate relative risk associated with a 1-mmol/liter increase in triglycerides was 1.13 (95 percent CI: 1.06, 1.21; p < 0.001) and 1.09 (95 percent CI: 1.00, 1.19; p = 0.04). When we further adjusted for HDL cholesterol, the multivariate relative risk in the highest versus lowest quartiles of triglycerides was 1.26 (95 percent CI: 0.90, 1.77; p = 0.18) for men and 1.50 (95 percent CI: 0.99, 2.27; p = 0.05) for women. The respective multivariate relative risk associated with a 1-mmol/liter increase in triglycerides was 1.15 (95 percent CI: 1.02, 1.29; p = 0.03) and 1.10 (95 percent CI: 0.95, 1.27; p = 0.20).
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DISCUSSION
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Nonfasting serum triglycerides were positively associated with the incidence of coronary heart disease for Japanese men and women, whose mean serum total cholesterol was low by Western standards. The positive relation with triglycerides was similarly observed for men and women after adjustment for age, serum total cholesterol levels, serum glucose category, other coronary risk factors, and time since last meal. Serum triglycerides were weakly but significantly associated with total mortality. To our knowledge, this is the first report of a significant relation of triglycerides with risk among Japanese who do not live in a Western environment. Our results are consistent with the results of two Caucasian cohorts (25
, 27
) with nonfasting serum triglycerides, and they are also consistent with recent reports on Caucasians in Denmark (27
) and Japanese-Americans (38
) and with the meta-analysis (29
) of 17 prospective studies on fasting triglycerides and coronary heart disease. The adjustment for a continuous serum glucose value instead of serum glucose category did not change materially the relative risks of coronary heart disease according to triglyceride levels, whereas this adjustment substantially attenuated them in a previous study of Caucasians (10
).
In our study, the positive association with triglycerides was similar among myocardial infarction, angina pectoris, and sudden cardiac death. However, the number of angina pectoris and sudden cardiac death events was relatively small, and the sex-specific relative risk estimates were not always statistically significant. Previous prospective studies in Swedish men (number of angina events = 28) (21
) and women (number of angina events = 55) (22
) did not yield any significant association between triglycerides and angina pectoris. No previous study examined the relation between triglycerides and sudden cardiac death alone.
The relation between triglycerides and the risk of coronary heart disease was not influenced materially by serum total cholesterol levels when men and women were combined; this result was consistent with our hypothesis. Our study showed that, even in a subgroup with lower cholesterol levels, triglycerides were associated with an increased risk of coronary heart disease, which strengthens the implication that the triglyceride level is predictive of coronary heart disease with populations of low total cholesterol levels. Moreover, for men the relation with triglycerides tended to be more evident among the subgroup with lower cholesterol levels than among that with higher levels, as reported by some previous Caucasian studies (8
, 9
). For women such a potential interaction was not observed, but this could be caused by random variation due to the small number of cases.
We did not examine HDL cholesterol for all of the participants but had data for 51 percent of them. After we conducted a subsample analysis adjusting HDL cholesterol levels, the association between triglycerides and risk of coronary heart disease remained statistically significant for women and of borderline significance for men. Stratification analysis by the median of HDL cholesterol levels also supported an independent association between triglycerides and the risk of coronary heart disease. The relative risk estimate per 1-mmol/liter increase in triglycerides in our study was somewhat higher than that reported from the meta-analysis (29
): 1.26 (95 percent CI: 0.97, 1.65) for men and 1.49 (95 percent CI: 1.03, 2.16) for women in our study and 1.14 (95 percent CI: 1.05, 1.28) for men and 1.37 (95 percent CI: 1.13, 1.66) for women in the meta-analysis.
In our study, over 80 percent of the participants were nonfasting. Thus, our findings were primarily for postprandial triglycerides and coronary heart disease (39
) like two other studies in Norway (25
) and the United States (24
). Some cross-sectional studies have indicated that postprandial triglyceride levels may be more strongly associated with coronary atherosclerosis than are fasting levels (40
, 41
). A high triglyceride level postprandially is closely linked with delayed clearance of chylomicron remnants (39
). Chylomicron remnants, enriched in triglycerides and cholesterol esters, are taken up by the arterial wall by means other than the LDL cholesterol receptor, and they are as atherogenic as LDL cholesterol in animal experiments (39
). Furthermore, high triglyceride levels in either the postprandial or fasting state are associated with atherogenic, small, LDL particles (3
, 42
), which may be more atherogenic than larger LDL particles because of increased susceptibility to oxidation (43
). High triglyceride levels are also associated with increased concentrations of factor VII and plasminogen activator inhibitor (44
), increased insulin resistance (45
), and increased blood leukocyte counts (46
), all of which may accelerate atherosclerotic and thrombotic processes. Low fish intake may lead to high triglyceride concentrations and also lead to high platelet aggregation (47
); both of these effects increase risk of coronary heart disease (47
). Unfortunately, no individual data on fish intake were available to examine this issue in the present study.
In conclusion, serum triglycerides predict the risk of coronary heart disease, independent of total cholesterol and HDL cholesterol, among Japanese men and women who possess low mean values of total cholesterol by Western standards.
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ACKNOWLEDGMENTS
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This study was supported in part by a contract from the Japanese Ministry of Education (grant-in-aid for research A: 04304036).
The authors thank Dr. Aaron R. Folsom, University of Minnesota, and Dr. Melissa A. Austin, University of Washington, for their valuable comments and Masakazu Nakamura for his excellent quality control for lipid measurements.
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NOTES
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Reprint requests to Dr. Hiroyasu Iso, Institute of Community Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki-ken, Japan (e-mail: fvgh5640{at}mb.infoweb.ne.jp).
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Received for publication March 2, 2000.
Accepted for publication July 18, 2000.