Serum Levels of Polyunsaturated Fatty Acids and Risk of Colorectal Cancer: A Prospective Study

Masayo Kojima1 , Kenji Wakai2, Shinkan Tokudome1, Koji Suzuki3, Koji Tamakoshi4, Yoshiyuki Watanabe5, Miyuki Kawado6, Shuji Hashimoto6, Norihiko Hayakawa7, Kotaro Ozasa5, Hideaki Toyoshima4, Sadao Suzuki1, Yoshinori Ito3 and Akiko Tamakoshi8 for the JACC Study Group

1 Department of Health Promotion and Preventive Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
2 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
3 Department of Public Health, Fujita Health University School of Health Sciences, Aichi, Japan.
4 Department of Public Health/Health Information Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
5 Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
6 Department of Hygiene, Fujita Health University School of Medicine, Aichi, Japan.
7 Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
8 Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Received for publication May 28, 2004; accepted for publication October 4, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To examine the relation between serum fatty acids and risk of colorectal cancer, the authors conducted a nested case-control study of 169 colorectal cancer cases and 481 controls matched by age and enrollment area as part of the Japan Collaborative Cohort Study. Serum samples were donated by subjects at baseline (between 1988 and 1990) and were stored at –80°C until 2002. Serum fatty acid levels were measured by using gas chromatography and were expressed as the weight percentage of total lipids. Conditional logistic regression analyses adjusted for lifestyle factors revealed that total {omega}-3 polyunsaturated fatty acids (odds ratio = 0.24, 95% confidence interval: 0.08, 0.76), {alpha}-linolenic acid (odds ratio = 0.39, 95% confidence interval: 0.16, 0.91), docosapentaenoic acid (odds ratio = 0.30, 95% confidence interval: 0.11, 0.80), and docosahexaenoic acid (odds ratio = 0.23, 95% confidence interval: 0.07, 0.76) all showed a significantly decreased risk for the highest versus the lowest quartile levels for colorectal cancer in men. For women, a weak negative association was observed between docosapentaenoic acid and colorectal cancer risk, although it was not statistically significant. No adverse effects of high serum levels of {omega}-6 polyunsaturated fatty acids on colorectal cancer risk were detected.

alpha-linolenic acid; chromatography; colorectal neoplasms; docosahexaenoic acids; eicosapentaenoic acid; fatty acids; prospective studies; serum


Abbreviations: CI, confidence interval; JACC Study, Japan Collaborative Cohort Study for the Evaluation of Cancer Risk; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acid; Q, quartile.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A number of experimental studies have reported an association between specific fatty acids and colorectal cancer risk. In particular, protective effects of {omega}-3 polyunsaturated fatty acids (PUFAs) (15) and adverse effects of {omega}-6 PUFAs (68) have been observed. However, the evidence from epidemiologic studies is limited and inconsistent (9). One major problem is the difficulty of measuring fatty acids accurately. The fatty acid composition of serum lipids is considered a reliable index reflecting dietary intake of fatty acids over periods of weeks or months (10, 11). Nevertheless, because of the high cost of measuring serum fatty acid levels, this procedure is performed in only those studies with relatively small numbers of subjects. Here, we report the results of a nested case-control study conducted as part of a nationwide cohort study, in which the association between serum fatty acid levels and risk of colorectal cancer was examined prospectively.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Details of the Japan Collaborative Cohort Study for the Evaluation of Cancer Risk (JACC Study), sponsored by Monbukagakusho (the Ministry of Education, Culture, Sports, Science and Technology of Japan), have been reported elsewhere (12, 13). The JACC Study involved 110,792 healthy residents who were aged 40–79 years at baseline and were recruited from 45 areas throughout Japan between 1988 and 1990. The subjects for the present study were restricted to 65,184 persons who lived in 24 study areas in which cancer registries were available. On enrollment, the participants completed a self-administered questionnaire that assessed demographic characteristics, lifestyle, and medical history. Blood samples were donated by 36.6 percent of the total study group (n = 23,863). Participants who reported a previous history of cancer (n = 409) were excluded from the analysis. Written informed consent for participation was obtained individually from most subjects, with the exception of those in study areas in which informed consent was provided at the group level after the aim of the study and the confidentiality of the data had been explained to community leaders. The study protocol was approved by the Ethics Committee of Medical Care and Research of the Fujita Health University School of Medicine, Japan.

Case ascertainment and control selection
Cases were defined as subjects who developed colorectal cancer (according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes C18–20) during the follow-up period (mean, 7.1 years; standard deviation, 2.3), which ran until the end of 1997. We ascertained the incidence of cancer from population-based cancer registries, supplemented by a systematic review of death certificates (14). For each case, two or three controls with no previous history of cancer were selected from the population at risk. The controls were matched to each case by sex, age (±3 years, as close as possible), and participating institution. A total of 169 colorectal cancer cases (83 men and 86 women) and 481 controls (241 men and 240 women) were involved in the analysis. The numbers of colon cancer cases and matched controls were 119 (52 men and 67 women) and 336 (151 men and 185 women), respectively.

Serum fatty acid analysis
Serum was separated from the blood samples at local laboratories in or near the surveyed municipalities and was stored for 11–14 years at –80°C. All samples were analyzed in November 2002 in one laboratory by trained staff blinded to case-control status. Samples were organized in batches of up to 50, which included two samples from a standard pool for quality control. Lipids in 0.2 ml of serum were extracted with Folch’s solution under a nitrogen atmosphere (15). After methyl esterification by 0.4 M potassium methoxide and 14 weight percentage boron trifluoride methanol, fatty acids were measured by using a gas chromatograph (model GC17A; Shimazu, Kyoto, Japan) equipped with an Omegawax 250 capillary column (30-m x 0.25-mm inside diameter; 0.25-µm thickness; Supelco, Bellefonte, Pennsylvania). Peaks were determined by using a flame-ionization detector and were quantified with an electric integrator (model CR-7A; Shimazu) using pure standard mixtures (Sigma, St. Louis, Missouri).

A total of 24 fatty acids were identified from 12:0 to 24:1 {omega}-9. The serum level of each fatty acid was expressed as the composition, by weight percentage, of total lipids. The limit of detection for the assay was 0.02 weight percent. The respective repeatability and day-to-day variation of the standard sample coefficients of variation were as follows: 5.5 percent for both measurements for 16:0; 6.2 percent and 5.6 percent for 18:2; 4.9 percent and 6.5 percent for 20:3; and 2.9 percent and 4.5 percent for 24:1.

In particular, four {omega}-3 PUFAs and six {omega}-6 PUFAs were measured: {alpha}-18:3 {omega}-3 ({alpha}-linolenic acid), 20:5 {omega}-3 (eicosapentaenoic acid), 22:5 {omega}-3 (docosapentaenoic acid), 22:6 {omega}-3 (docosahexaenoic acid), 18:2 {omega}-6 (linoleic acid), {gamma}-18:2 {omega}-6 ({gamma}-linolenic acid), 20:2 {omega}-6 (eicosadienoic acid), 20:3 {omega}-6 (dihomo-{gamma}-linolenic acid), 20:4 {omega}-6 (arachidonic acid), and 22:4 {omega}-6 (docosatetoraenoic acid). In addition, we calculated the content of total saturated fatty acids (12:0 + 14:0 + 16:0 + 18:0 + 20:0 + 22:0 + 24:0), monounsaturated fatty acids (MUFAs; 16:1 {omega}-7 + 18:1 {omega}-9 + 20:1 {omega}-9 + 22:1 {omega}-9 + 24:1 {omega}-9), and total {omega}-3 and {omega}-6 PUFAs. The ratio of {omega}-6 to {omega}-3 PUFAs was also determined.

Statistical methods
Background characteristics were compared between cases and controls by using the Cochran-Mantel-Haenszel test (16) and analysis of covariance (17), with adjustment for matching factors (age and area of enrollment) by sex. Spearman’s correlation coefficients were calculated to determine the association between fatty acids. Conditional logistic regression models were used to calculate odds ratios for the incidence of colorectal cancer (18) for the serum level of each specific fatty acid. The odds ratios for colon cancer risk were also examined separately from those for rectal cancer. Cases and controls were divided into four groups according to the level of fatty acids in controls. Odds ratios were calculated for the second quartile ((Q)2), third quartile (Q3), and highest quartile (Q4) versus the lowest quartile (Q1). To test for linear trends in odds ratios over quartiles, we coded each quartile as 0, 1, 2, or 3 and incorporated these data into the logistic model as a single variable.

We adjusted for the following factors by including them in the logistic models (19): age at completing final education (≤18 years or ≥19 years); history of colorectal cancer in parents or siblings (yes or no); body mass index (weight (kg)/height (m)2; <20.0 kg/m2, 20.0–24.9 kg/m2, or ≥25.0 kg/m2) calculated from reported height and weight at baseline; smoking status (never, former, or current); daily alcohol consumption (never, former, or current); frequency of intake of green leafy vegetables (almost every day or ≤3–4 days per week), and time spent exercising (<3 hours per week or ≥3 hours per week) (20). The results were not significantly affected by adjustment for potential confounding factors; therefore, only the multivariate-adjusted odds ratios are presented in the tables in this paper. To eliminate the influence of undiagnosed colorectal cancers at baseline, the analyses were repeated by excluding men and women who developed colorectal cancer within the first 2 or 5 years of follow-up, respectively, along with their matched controls.

All analyses were performed by using SAS software, release 8.2 (SAS Institute, Inc., Cary, North Carolina). In the conditional logistic regression analysis, missing values for each categorical covariate were treated as an additional category of the variable and were included in the model. Two-tailed probability (p) values of <0.1 were considered marginally significant, and p values of <0.05 were considered statistically significant.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 gives the baseline characteristics of all colorectal cancer cases and controls by sex. For both men and women, the age distributions of the cases and controls were well matched. Cases were more likely than controls to have a family history of colorectal cancer. There were no significant differences between cases and controls regarding body mass index, educational level, smoking and alcohol drinking habits, or frequency of green leafy vegetable intake or physical exercise.


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TABLE 1. Baseline characteristics of colorectal cancer cases and controls from the Japan Collaborative Cohort Study for the Evaluation of Cancer Risk, 1988–1997
 
Spearman’s correlation coefficients between the fatty acids were computed (data not shown). The directions of the associations were not affected by sex, and all correlation coefficients were statistically significant. For both men and women, {omega}-3 PUFAs were mildly inversely correlated with {omega}-6 PUFAs (r = –0.24 and r = –0.12, respectively), MUFAs (r = –0.30 and r = –0.44, respectively), and saturated fatty acids (r = –0.18 and r = –0.27, respectively). In men and women, {omega}-6 PUFAs were moderately inversely correlated with MUFAs (r = –0.68 for both sexes) and saturated fatty acids (r = –0.72 and r = –0.77, respectively). In addition, MUFAs and saturated fatty acids were mildly positively correlated in both men and women (r = 0.35 and r = 0.46, respectively).

Table 2 shows the associations between the serum levels of each group of fatty acids and the risk of colorectal cancer by sex. For men, total saturated fatty acids and {omega}-6 PUFAs failed to show significant associations with colorectal cancer risk. A marginally significant positive trend was observed between serum level of total MUFAs and colorectal cancer risk (p for linear trend = 0.06). Total {omega}-3 PUFAs were inversely associated with colorectal cancer risk, showing a 76 percent risk reduction when Q4 and Q1 were compared (odds ratio = 0.24, 95 percent confidence interval (CI): 0.08, 0.76; p for linear trend = 0.08). For the {omega}-6/{omega}-3 ratio, Q2 showed a marginally significant association, with a 2.36-fold increased risk of colorectal cancer relative to Q1 (95 percent CI: 0.99, 5.66), although the dose-response relation was unclear. In the analysis of colon cancer risk alone (data not shown), there was no statistically significant association with the serum levels of any of the fatty acids. However, the directions of the nonsignificant trends were similar to those observed in the combined analyses. The odds ratios for Q4 versus Q1 of each group of fatty acids for the risk of colon cancer in men were as follows: 1.00 for saturated fatty acids (95 percent CI: 0.28, 3.52; p for linear trend = 0.84), 1.19 for MUFAs (95 percent CI: 0.34, 4.22; p for linear trend = 0.60), 0.40 for {omega}-3 PUFAs (95 percent CI: 0.10, 1.55; p for linear trend = 0.43), and 1.04 for {omega}-6 PUFAs (95 percent CI: 0.34, 3.16; p for linear trend = 0.86).


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TABLE 2. Associations of serum level of fatty acids with colorectal cancer risk, by sex, Japan Collaborative Cohort Study for the Evaluation of Cancer Risk, 1988–1997
 
For women, the association between the levels of all groups of fatty acids, except saturated fatty acids, and colorectal cancer risk tended to be U- or J-shaped, although any associations failed to reach the statistically significant level (table 2). Similar results were obtained when the analyses were repeated for colon cancer cases alone (data not shown). The odds ratios for Q4 versus Q1 of groups of fatty acids were as follows: 0.56 for saturated fatty acids (95 percent CI: 0.20, 1.59; p for linear trend = 0.12), 0.70 for MUFAs (95 percent CI: 0.26, 1.84; p for linear trend = 0.53), 0.90 for {omega}-3 PUFAs (95 percent CI: 0.37, 2.20; p for linear trend = 0.46), and 1.01 for {omega}-6 PUFAs (95 percent CI: 0.36, 2.86; p for linear trend = 0.46).

To exclude the influence of undiagnosed colorectal cancer at baseline, the analyses were repeated by excluding men and women who developed colorectal cancer during the first 2 or 5 years of follow-up, respectively, along with their matched controls (table 3). For men, excluding those who developed colorectal cancer within the first 5 years strengthened both the positive association of total MUFAs and the inverse association of total {omega}-3 PUFAs with colorectal cancer risk. For women, excluding those who developed colorectal cancer within the first 2 years revealed a significant association for {omega}-3 PUFAs, with a 70 percent decreased risk of colorectal cancer at the Q2 compared with the Q1 level (odds ratio = 0.30, 95 percent CI: 0.11, 0.79).


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TABLE 3. Associations of serum level of fatty acids with colorectal cancer risk, by length of cases’ follow-up period, Japan Collaborative Cohort Study for the Evaluation of Cancer Risk, 1988–1997
 
Table 4 shows the association of levels of specific {omega}-3 fatty acids with colorectal cancer risk. For men, of the four {omega}-3 PUFAs examined, all except eicosapentaenoic acid showed significant or marginally significant inverse associations with colorectal cancer risk. Eicosapentaenoic acid narrowly failed to show a significant inverse association with colorectal cancer risk (Q4 vs. Q1 odds ratio = 0.44, 95 percent CI: 0.18, 1.08; p for linear trend = 0.13). The inverse associations between serum levels of specific {omega}-3 PUFAs and colorectal cancer risk became more significant when cases were restricted to only those followed up for more than 5 years. For men, the odds ratios for Q4 versus Q1 were as follows: 0.10 for {alpha}-linoleic acid (95 percent CI: 0.01, 0.86; p for linear trend = 0.23), 0.44 for eicosapentaenoic acid (95 percent CI: 0.10, 1.94; p for linear trend = 0.13), 0.24 for docosapentaenoic acid (95 percent CI: 0.05, 1.09; p for linear trend = 0.07), and 0.07 for docosahexaenoic acid (95 percent CI: 0.01, 0.70; p for linear trend = 0.10).


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TABLE 4. Associations of serum levels of {omega}-3 polyunsaturated fatty acids with colorectal cancer risk, by sex, Japan Collaborative Cohort Study for the Evaluation of Cancer Risk, 1988–1997
 
For women, a significantly increased risk for Q3 compared with Q1 was observed for {alpha}-linolenic acid (table 4). For the other {omega}-3 PUFAs, the odds ratios for the highest versus the lowest quartiles were less than 1.0. When those participants who developed colorectal cancer within the first 5 years of follow-up were excluded from the analyses, all {omega}-3 PUFAs showed a decreased risk at the highest level (data not shown). The odds ratios for Q4 versus Q1 for women were as follows: 0.64 for {alpha}-linolenic acid (95 percent CI: 0.11, 3.75; p for linear trend = 0.51), 0.55 for eicosapentaenoic acid (95 percent CI: 0.10, 3.11; p for linear trend = 0.40), 0.86 for docosapentaenoic acid (95 percent CI: 0.17, 4.45; p for linear trend = 0.58), and 0.53 for docosahexaenoic acid (95 percent CI: 0.07, 3.98; p for linear trend = 0.80). No significant linear trend was detected between the serum levels of any {omega}-6 PUFAs and colorectal cancer risk for men or women (table 5). Only eicosadienoic acid showed a significant association with a decreased risk of colorectal cancer at the Q3 versus Q1 level for men (odds ratio = 0.18, 95 percent CI: 0.06, 0.56).


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TABLE 5. Associations of serum levels of {omega}-6 polyunsaturated fatty acids with colorectal cancer risk, by sex, Japan Collaborative Cohort Study for the Risk of Cancer Risk, 1988–1997
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The main strength of our study is its prospective design and the use of biomarkers to evaluate each fatty acid level. Because we collected serum samples and background data from subjects when they were free of cancer, we were able to eliminate any influence of the cancer itself or recall bias on the results. We confirmed our results by repeating the analyses after excluding persons who developed colorectal cancer within the first 2 or 5 years of follow-up, along with their matched controls, to eliminate any potential effects of undiagnosed colorectal cancer cases at baseline.

Our study design is similar to that of the nested case-control study based on data from the Multiple Risk Factor Intervention Trial (MRFIT) (21). Simon et al. examined 108 cancer cases and 215 controls and found no association between any serum fatty acid component and the risk of fatal cancer. Unfortunately, because of the limited number of subjects, they were unable to estimate risk by organ site. This prospective study is the first known to report an association between colorectal cancer risk and specific serum fatty acids.

We found a marginally significant inverse association between serum level of {omega}-3 PUFAs and the risk of colorectal cancer in men. The odds ratios for the highest versus lowest quartiles of all {omega}-3 PUFAs examined were less than 1.0 and were statistically significant (p < 0.05), except for eicosapentaenoic acid (p = 0.13). These findings support the potential preventive effects of fish oil supplements rich in {omega}-3 PUFAs against colorectal cancer (22, 23), which have been suggested by a number of clinical studies (35, 24, 25). The chemopreventive activity of nonsteroidal antiinflammatory drugs on colorectal tumors has been well documented in a number of experimental studies (2629). Suppression of cyclooxygenase and inhibition of prostaglandin E2 synthesis by nonsteroidal antiinflammatory drugs is thought to be the main mechanism for this activity. {omega}-3 PUFAs are thought to influence the carcinogenic process via their effects on the synthesis of prostaglandins and thromboxanes (1) through a mechanism similar to that of nonsteroidal antiinflammatory drugs. Increased intake of eicosapentaenoic and docosahexaenoic acids might also promote apoptosis in cells of the normal human colonic mucosa (30).

We found no significant association between {omega}-3 PUFAs and the risk of colorectal cancer in women. {alpha}-linolenic and linoleic acid were associated with colorectal cancer incidence in the opposite direction for men and women. MUFAs showed a marginally significant positive association for men only. On the basis of the available data, we cannot suggest a plausible explanation for the gender difference in the association between fatty acids and colorectal cancer risk. Genetic and hormonal factors, nutritional status, and disease are all thought to influence fatty acid metabolism (31). In addition, it has been suggested that female sex hormones play a role in the etiology of colorectal cancer (32, 33). Interestingly, the odds ratios for the highest versus lowest quartiles were less than 1.0 for all of the {omega}-3 PUFAs examined in women when those women who developed colorectal cancer within the first 5 years of follow-up were excluded. It is possible that physical disorders or medications not evaluated in the present analyses might have influenced the results. Unfortunately, we did not collect data on use of nonsteroidal antiinflammatory drugs and other medications that might have interfered with the association between {omega}-3 PUFAs and colorectal cancer risk. Further investigation of diet and metabolism will therefore be necessary to clarify these gender interactions. In addition, we did not observe an obvious dose response between serum levels of {omega}-3 PUFAs and colorectal cancer risk. Additional studies should thus examine whether an optimal level of {omega}-3 PUFAs is associated with colorectal cancer prevention.

The risks of colorectal cancer are reported to vary by subsite (34, 35). The available data showed no obvious differences between the separate risk of colon cancer and the combined risk of colorectal cancer regarding the association with fatty acids. Although we were unable to estimate the independent risks by subsite in our study because of the limited number of cases, they should be confirmed in future studies with larger sample sizes.

Some limitations that affected interpretation of our results must be noted. First, our subjects were selected from among the participants of a large cohort study. As Kato et al. (36) discussed previously, subjects in cohort studies tend to be homogeneous and health conscious, which might reduce the between-person variation in food consumption and other health-related factors and make detection of associations between individual fatty acids and disease risk more difficult. Moreover, the subjects in the present study were limited to those who donated blood samples: only 36.6 percent of the total cohort. In fact, those who did not donate blood samples were more likely to be highly educated, to consume alcohol daily, and to exercise less compared with those who donated blood samples, regardless of gender. In addition, compared with nonparticipants, male participants tended to be older and female participants tended to be younger. The differences in the background characteristics of the subjects should be considered to generalize our findings. Second, because this was a multicenter study (12), the procedures used to collect blood were not uniform. However, we confirmed that no area had a greatly different distribution of fatty acid levels. In addition, we matched cases and controls by participating institution; therefore, any bias due to differences between areas should have been accounted for.

Third, we used serum samples that were stored at –80°C for 11–14 years to evaluate the levels of fatty acids. Iso et al. (37) examined 31 serum samples taken from subjects in the present cohort in 1990 and again in 1998. They reported an increase in the composition of saturated fatty acids (29.2 percent vs. 30.3 percent) and 20:3 (dihomo-{gamma} linolenic acid) (0.85 percent vs. 0.98 percent), a decline in the composition of MUFAs (22.9 percent vs. 22.4 percent), and no changes in the other fatty acids over this 8-year time interval. Zeleniuch-Jacquotte et al. (11) reported that storage for up to 12 years at –80°C effectively protected PUFAs from oxidation. However, the long-term effects of storage for up to 14 years have not been confirmed. Fourth, although we used the fatty acid composition of serum total lipids as a biomarker, several alternative methods are available for biologic assessment of fat intake. Adipose tissue and the erythrocyte membrane reflect long- and medium-term fatty acid intake, respectively, whereas serum reflects only short-term (weeks to months) intake (10). Although measuring these alternative biomarkers is more expensive and invasive, they might be a better index for use in predicting colorectal cancer. Therefore, our results should be confirmed by using these media. Fifth and finally, we evaluated the fatty acids and background characteristics of the subjects only once, at baseline. These measurements might not accurately reflect the long-term habits of the subjects. Thus, repeated measurements should be considered to reduce measurement errors (11).


    ACKNOWLEDGMENTS
 
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (2; 14031222) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The JACC Study has also been supported by Grants-in-Aid for Scientific Research from the same ministry (61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, and 11181101).

The authors express their appreciation to Dr. Kunio Aoki, Professor Emeritus, Nagoya University School of Medicine and the former chairman of the JACC Study Group; and to Dr. Haruo Sugano, the former director of the Cancer Institute of the Japanese Foundation for Cancer Research, who greatly contributed to initiating the study.

The present members of the JACC Study and their affiliations are as follows: Dr. Akiko Tamakoshi (present chairman of the study group), Nagoya University Graduate School of Medicine; 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, University of Human Arts and Sciences Graduate School; Dr. Hiroshi Suzuki, Niigata University Graduate School of Medical and Dental Sciences; Dr. Hiroyuki Shimizu, Gifu University School of Medicine; Dr. Hideaki Toyoshima, Nagoya University Graduate School of Medicine; Dr. Shinkan Tokudome, Nagoya City University Graduate School of Medical Science; 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 and Dr. Tsuneharu Miki, Kyoto Prefectural University of Medicine Graduate School of Medical Science; 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. Naoyuki Okamoto, Kanagawa Cancer Center; Dr. Hideo Shio, Moriyama Municipal Hospital; Dr. Yoshiyuki Ohno (former chairman of the study group), Asahi Rosai Hospital; 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 members of the JACC Study, other than the following eight, are listed in reference 9 (affiliations are those at the time of participation in the JACC Study): Dr. Takashi Shimamoto, Institute of Community Medicine, University of Tsukuba; Dr. Heizo Tanaka, Medical Research Institute, Tokyo Medical and Dental University; Dr. Shigeru Hisamichi, Tohoku University Graduate School of Medicine; Dr. Masahiro Nakao, Kyoto Prefectural University of Medicine; Dr. Takaichiro Suzuki, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases; Dr. Tsutomu Hashimoto, Wakayama Medical University; Dr. Teruo Ishibashi, Asama General Hospital; and Dr. Katsuhiro Fukuda, Kurume University School of Medicine.


    NOTES
 
Reprint requests to Dr. Masayo Kojima, Department of Health Promotion and Preventive Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho, Nagoya 467-8601, Japan (e-mail: masayok{at}med.nagoya-cu.ac.jp). Back


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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