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American Journal of Epidemiology Advance Access originally published online on April 11, 2008
American Journal of Epidemiology 2008 167(12):1397-1406; doi:10.1093/aje/kwn073
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Alcohol Drinking and Colorectal Cancer in Japanese: A Pooled Analysis of Results from Five Cohort Studies

Tetsuya Mizoue1, Manami Inoue2, Kenji Wakai3, Chisato Nagata4, Taichi Shimazu2,5, Ichiro Tsuji5, Tetsuya Otani6, Keitaro Tanaka7, Keitaro Matsuo8, Akiko Tamakoshi9, Shizuka Sasazuki2, Shoichiro Tsugane for the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan2

1 Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, Tokyo, Japan
2 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
3 Department of Preventive Medicine/Biostatistics and Medical Decision Making, Graduate School of Medicine, Nagoya University, Nagoya, Japan
4 Department of Epidemiology and Preventive Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan
5 Division of Epidemiology, Department of Public Health and Forensic Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
6 Department of Public Health, Graduate School of Medicine, Gunma University, Maebashi, Japan
7 Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
8 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
9 Division of Clinical Trials, National Center for Geriatrics and Gerontology, Aichi, Japan

Correspondence to Dr. Tetsuya Mizoue, Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan (e-mail: mizoue{at}ri.imcj.go.jp).

Received for publication November 5, 2007. Accepted for publication February 28, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Colorectal cancer is an alcohol-related malignancy; however, the association appears to be stronger among Asian populations with a relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant. To examine the association between alcohol consumption and colorectal cancer in Japanese, the authors analyzed original data from five cohort studies that measured alcohol intake using validated questionnaires at baseline. Hazard ratios were calculated in the individual studies, with adjustment for a common set of variables, and then combined using a random-effects model. During 2,231,010 person-years of follow-up (ranging variously from 1988 to 2004), 2,802 colorectal cancer cases were identified. In men, multivariate-adjusted pooled hazard ratios for alcohol intakes of 23–45.9 g/day, 46–68.9 g/day, 69–91.9 g/day, and ≥92 g/day, compared with nondrinking, were 1.42 (95% confidence interval (CI): 1.21, 1.66), 1.95 (95% CI: 1.53, 2.49), 2.15 (95% CI: 1.74, 2.64), and 2.96 (95% CI: 2.27, 3.86), respectively (p for trend < 0.001). The association was evident for both the colon and the rectum. A significant positive association was also observed in women. One fourth of colorectal cancer cases in men were attributable to an alcohol intake of ≥23 g/day. An alcohol-colorectal cancer association seems to be more apparent in Japanese than in Western populations. Whether this difference can be ascribed to genetic or environmental factors needs to be clarified.

alcohol drinking; colonic neoplasms; colorectal neoplasms; rectal neoplasms

Abbreviations: CI, confidence interval; HR, hazard ratio; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Center-based Prospective Study


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Colorectal cancer is a common malignancy in developed countries (1). In Japan, after a marked increase over the last several decades (2), the incidence of colorectal cancer is currently among the highest in the world (1). Epidemiologic data generally support the hypothesis that alcohol drinking increases colorectal cancer risk (3–5), and in the latest evaluation by the International Agency for Research on Cancer, colorectal cancer was added to the list of alcohol-related malignancies (6, 7). However, the influence of alcohol drinking could be greater among Asian populations because of their relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant (8), which is associated with increased blood levels of acetaldehyde, a potential carcinogen (9), after alcohol ingestion (10). In line with this concern, in a meta-analysis of cohort studies, Moskal et al. (5) reported a stronger association with alcohol drinking for colon cancer (but not rectal cancer) in Asian studies as compared with Western studies.

In our 2006 review of epidemiologic studies carried out among Japanese (11), we identified a fairly consistent association between heavy alcohol intake and increased risk of colorectal cancer, and in all recent cohort studies (12–15), men in the highest category of alcohol intake have had nearly twice the risk of colon cancer as men in the lowest category. However, several issues remain unresolved. First, because cutpoints for alcohol intake varied by study, we were unable to obtain summary estimates according to amount of alcohol consumed. Second, the association for colon cancer appears to be more consistent than that for rectal cancer, but random variation may account for the difference. Third, the association was unclear among women, who consumed much lower amounts of alcohol than men, on average. From an international perspective, a seemingly stronger association with alcohol drinking in Japanese may simply reflect greater alcohol intake among Japanese drinkers than among their Western counterparts. A comparison of risks incurred at identical levels of exposure is required for confirmation. To address these issues, we conducted a pooled analysis of data from five large-scale cohort studies carried out in Japan.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
In 2006, the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan initiated a pooling project using original data from major cohort studies to evaluate the association between lifestyle and major forms of cancer in Japanese, in parallel with systematic reviews of the relevant literature. Topics for the pooled analysis were determined on the basis of discussion among all authors from the viewpoints of scientific and public health importance. To maintain high quality and comparability of data, we set inclusion criteria for the present purpose a priori: population-based cohort studies that were conducted in Japan, started between the mid-1980s and the mid-1990s, included more than 30,000 participants, obtained information on diet, including alcohol intake, using a validated questionnaire or a similar one at baseline, and collected incidence data for colorectal cancer during the follow-up period. We identified four ongoing studies that met these criteria: 1) the Japan Public Health Center-based Prospective Study (JPHC) (16), 2) the Japan Collaborative Cohort Study (JACC) (17), 3) the Miyagi Cohort Study (18), and 4) the Takayama Study (19). The JPHC was treated as two independent studies (JPHC I and JPHC II) because of a difference in the dietary questionnaires used; thus, data from a total of five studies were analyzed. We excluded data for subjects with extreme energy intakes (>3 standard deviations from the mean log-transformed energy intake in each study), missing information on alcohol consumption, or a history of cancer at baseline. Selected characteristics of these studies are presented in table 1. Each study was approved by the relevant institutional ethical review board. Results on the association between alcohol intake and colorectal cancer risk in each cohort have been reported (12–15). For the present analysis, we used updated data sets with an extended follow-up period for JPHC I, JPHC II, and JACC.


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  		TABLE 1. Characteristics of five Japanese cohort studies included in a pooled analysis of alcohol consumption and colorectal cancer risk, 1988–2004

 
Case ascertainment
Subjects were followed from the baseline survey (JPHC I: 1990, JPHC II: 1993–1994, JACC: 1988–1990, Miyagi: 1990, Takayama: 1992) to the last date of follow-up for incidence (JPHC I: 2004, JPHC II: 2004, JACC: 2001, Miyagi: 2001, Takayama: 1999) in each study. Residence status in each study, including survival, was confirmed through the residential registry. Information on cancer diagnosis was collected for the whole population in JPHC I, JPHC II, and the Miyagi Cohort Study; in these studies, cases were identified through active patient notification from major local hospitals and/or through population-based cancer registries. In the Takayama Study, active patient notification for colorectal cancer was conducted by major local hospitals. In JACC, because information on cancer diagnosis was collected in 22 out of 45 study areas, we used data from those 22 areas only. Cases were coded using the International Classification of Diseases for Oncology, Third Edition (20). Each study also collected information about causes of death from death certificates and coded them according to the International Classification of Diseases, Tenth Revision (21), which was used to complement the hospital and registry data on cancer diagnosis. The study outcome was defined as incident colorectal cancer (International Classification of Diseases for Oncology, Third Edition, codes C18.0–C18.9, C19.9, and C20.9; International Classification of Diseases, Tenth Revision, codes C18–C20) diagnosed during the follow-up period of each study.

Assessment of alcohol intake
Alcohol drinking status was assessed by means of self-administered questionnaires at baseline. Although the style of the questions differed by study, investigators in each study were able to calculate average daily alcohol consumption in grams of ethanol for regular drinkers on the basis of beverage type, frequency, and amount. The questionnaire in each study contained queries on the intake of alcoholic beverages popular in Japan, including beer, sake, and shochu, but the style of the questions differed across studies. Therefore, in the present study we used only total alcohol intake from all beverages as the exposure. In Japan, the go is the most commonly used unit of alcohol consumption; 1 go of sake (Japanese wine), equivalent to 180 ml, contains approximately 23 g of ethanol. Consumption was divided into categories using identical cutpoints across the studies (nondrinkers (never and ex-drinkers), occasional drinkers (<once/week), and regular drinkers (≥once/week: for men, 0.1–22.9 g/day, 23–45.9 g/day, 46–68.9 g/day, 69–91.9 g/day, or ≥92 g/day; for women, 0.1–22.9 g/day or ≥23 g/day)). Analysis using the same exposure categories as those used in a pooled analysis among Western populations (22) was also conducted for comparison. Correlation coefficients for the correlation between alcohol consumption estimated from the questionnaire and that from the dietary record were: JPHC—0.77 in men and 0.55 in women (23); Miyagi—0.77 in men and 0.71 in women (24); and Takayama—0.72 in men and 0.64 in women (19). The JACC, for which information on the validation of alcohol consumption was not available, utilized the same questions on alcohol consumption as the Miyagi Cohort Study. The analysis was repeated by using never drinkers as the reference group in the JACC, the Miyagi Cohort Study, and JPHC II, in which ex-drinkers were distinguishable from never drinkers.

Statistical analysis
Person-years of follow-up were calculated from the date of the baseline survey in each study to the date of diagnosis of colorectal cancer, migration from the study area, death, or the end of follow-up, whichever came first. Age was used as the primary time variable. In each individual study, sex-specific hazard ratios and 95 percent confidence intervals for colorectal cancer, colon cancer, and rectal cancer were estimated for each alcohol intake category using a Cox proportional hazards model. In all analyses, adjustments were made for age (continuous), area within each study (for JPHC I, JPHC II, and JACC), smoking (for men: never smoker, past smoker, current smoker of 1–19 cigarettes/day, or current smoker of ≥20 cigarettes/day; for women: never smoker, past smoker, or current smoker), body mass index (weight (kg)/height (m)2; <22, 22–24.9, 25–27.9, or ≥28), energy intake (continuous), and energy-adjusted dietary intakes of red meat (quartiles), calcium (quartiles), fiber (quartiles), and folate (quartiles) in each study. An indicator term for missing data was created for each covariate. Physical activity was not included in the common set of covariates because of large variation in the assessment of physical activity among the studies, but investigators from each study confirmed that additional adjustment for physical activity did not alter the results. SAS (version 9.1; SAS Institute, Inc., Cary, North Carolina) or Stata (version 9.2; Stata Corporation, College Station, Texas) statistical software was used for these estimations.

A random-effects model (25) was used to obtain a single pooled estimate of the hazard ratios from the individual studies for each category. The study-specific hazard ratios were weighted by the inverse of the sum of their variance and the estimated between-studies variance component. A study that had no cases for a category was not included in the pooled estimate for that category. The trend association was assessed in a similar manner: Investigators from each study calculated the regression coefficient per 15-g increase in alcohol intake and its standard error, and then these values from the individual studies were combined using a random-effects model. We tested for heterogeneity among studies by means of the Q statistic (25). Meta-regression was used to assess interactions with other risk factors. To estimate the impact of alcohol drinking on the risk of colorectal cancer, we calculated the population attributable fraction percentage according to the formula pd x (HR – 1)/HR, where pd is the proportion of cases exposed to the risk factor(s) (26) and HR is the hazard ratio. Stata was used for meta-analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The present study included 209,763 subjects (98,265 men and 111,498 women) and 2,802 colorectal cancer cases (1,724 men and 1,078 women) accumulated during 2,231,010 person-years of follow-up (table 1). The proportions of colon cancer cases were 63 percent for men and 68 percent for women. Half of the men consumed ≥23 g of alcohol per day. In contrast, 71 percent of women were nondrinkers, and the majority of female drinkers consumed alcohol occasionally (<once/week) or at a level of 0.1–22.9 g/day; only 4 percent consumed ≥23 g/day.

As table 2 shows, alcohol intake was associated with increased risk of colorectal cancer in a dose-response manner in men (p for trend < 0.001). A statistically significant increase in risk was observed among drinkers who consumed ≥23 g/day of alcohol; hazard ratios for 23–45.9 g/day, 46–68.9 g/day, 69–91.9 g/day, and ≥92 g/day (compared with nondrinking) were 1.42 (95 percent confidence interval (CI): 1.21, 1.66), 1.95 (95 percent CI: 1.53, 2.49), 2.15 (95 percent CI: 1.74, 2.64), and 2.96 (95 percent CI: 2.27, 3.86), respectively. The test for heterogeneity across studies was not statistically significant for the hazard ratio summarizing risk per 15-g/day increase in alcohol intake (p > 0.2). When ex-drinkers were defined separately from never drinkers, similar results were obtained: Hazard ratios for drinkers of 23–45.9 g/day, 46–68.9 g/day, 69–91.9 g/day, and ≥92 g/day versus nondrinkers were 1.57 (95 percent CI: 1.27, 1.94), 2.00 (95 percent CI: 1.30, 3.08), 2.19 (95 percent CI: 1.65, 2.90), and 2.98 (95 percent CI: 1.83, 4.85), respectively. A dose-response relation with alcohol consumption was evident for both the colon and the rectum (p for trend < 0.001), and the hazard ratios associated with alcohol intake of ≥46 g/day were similar. However, an alcohol intake of 23–45.9 g/day was significantly associated with the risk of colon cancer (hazard ratio (HR) = 1.60, 95 percent CI: 1.31, 1.95) but not the risk of rectal cancer (HR = 1.18, 95 percent CI: 0.90, 1.56). When never drinkers were used as the reference group, the risk of colon cancer with these intake levels was increased (HR = 1.93).


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  		TABLE 2. Results from a pooled analysis (random-effects model) of colorectal cancer incidence by alcohol intake in Japanese men, 1988–2004

 
In analysis for men using the same exposure categories as those used in the pooled analysis of Western studies (22), hazard ratios for colorectal cancer associated with alcohol intakes of 0.1–4.9 g/day, 5–14.9 g/day, 15–29.9 g/day, 30–44.9 g/day, and ≥45 g/day were 1.11 (95 percent CI: 0.74, 1.67), 1.10 (95 percent CI: 0.86, 1.42), 1.35 (95 percent CI: 1.10, 1.66), 1.61 (95 percent CI: 1.32, 1.95), and 2.09 (95 percent CI: 1.65, 2.64), respectively. A significant increase in colon cancer risk was observed at an alcohol intake of ≥15 g/day, whereas increased risk of rectal cancer was confined to an intake of ≥45 g/day (data not shown).

In women, drinkers who consumed ≥23 g/day of alcohol had a significantly increased risk of colorectal cancer in comparison with nondrinkers (HR = 1.57, 95 percent CI: 1.11, 2.21; table 3). Risk for that level of alcohol intake was significantly elevated for both colon cancer (HR = 1.66, 95 percent CI: 1.12, 2.46) and rectal cancer (HR = 2.39, 95 percent CI: 1.18, 4.88). Hazard ratios per 15-g/day increase in alcohol intake among women were also statistically significant for colorectal cancer, colon cancer, and rectal cancer and were similar to those in men. When never drinkers were used as the reference group, results were not changed materially (data not shown).


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  		TABLE 3. Results from a pooled analysis (random-effects model) of colorectal cancer incidence by alcohol intake in Japanese women, 1988–2004

 
In stratified analyses, the association between alcohol consumption and colorectal cancer risk was pronounced in lean persons: Among men with a body mass index of <22, the hazard ratio for alcohol consumption of ≥69 g/day was 3.25 (95 percent CI: 2.12, 4.99), and the p value for heterogeneity across categories of body mass index was 0.04 at that level of intake (table 4). Although the association was relatively weak in nonlean persons, a statistically significant increase in risk with greater alcohol consumption (≥46 g/day) was also observed among men with body mass indices of 22–24.9 or ≥25. Hazard ratios for the greatest alcohol intake did not differ appreciably across tertiles of folate intake, although at lower levels of alcohol consumption, hazard ratios were somewhat lower in men with the highest folate intakes than in men with lower intakes.


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  		TABLE 4. Pooled multivariate hazard ratios{dagger} (random-effects model) for the association between alcohol intake and colorectal cancer incidence by body mass index and folate intake in Japanese men, 1988–2004

 
Based on the risk estimates in the present study, the percentage of colorectal cancer cases attributable to an alcohol intake of ≥23 g/day was 27 percent for men and 1.4 percent for women.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this pooled analysis of major population-based cohort studies carried out in Japan, we found a clear dose-response relation between alcohol consumption and colorectal cancer risk in men, with heavy drinkers who consumed ≥46 g/day of alcohol showing a risk nearly twice that of nondrinkers. The association was evident for both the colon and the rectum. A significant positive association was also observed in women.

In experimental animals, there is sufficient evidence for the carcinogenicity of acetaldehyde (9), a metabolite of alcohol. Specific mechanisms by which alcohol drinking influences colorectal carcinogenesis in humans remain elusive. However, alcohol or acetaldehyde may induce DNA hypomethylation, an early step in colonic carcinogenesis, through its antifolate effects (27). Moreover, acetaldehyde generated by intestinal bacteria may increase the risk of colorectal cancer via folate deficiency (28) or its carcinogenic effects on the intestine. Alcohol and its metabolites may also interfere with intestinal absorption of potentially anticarcinogenic nutrients, including folate (29) and calcium (30).

In a meta-analysis of cohort studies, Moskal et al. (5) identified study region as a significant modifier of colon cancer risk and reported a higher summary relative risk of colon cancer among Asian studies than among European or US studies. However, such a finding may simply reflect a difference in alcohol intake in the highest category across studies. Thus, a comparison using the same exposure cutpoints would be of interest (see figure 1). In the pooled analysis of Western studies (22), relative risks of colorectal cancer for male drinkers consuming 30–44.9 g/day and ≥45 g/day versus nondrinkers were 1.11 (95 percent CI: 0.86, 1.45) and 1.41 (95 percent CI: 1.11, 1.79), respectively. In Japanese men in the present study, hazard ratios at the corresponding levels of alcohol consumption were 1.61 (95 percent CI: 1.32, 1.95) and 2.09 (95 percent CI: 1.65, 2.64), respectively. Moreover, the pooling study among Western populations (22) did not show a measurable increase in colon cancer risk with alcohol intakes of 30–44.9 g/day (the relative risk for women and men combined was 1.08) (22), whereas in the present study we detected a significantly increased risk at these intake levels (HR = 1.91, 95 percent CI: 1.41, 2.89). Likewise, the relative risk of colon cancer associated with an alcohol intake of 15–29.9 g/day was 1.08 in the European Prospective Investigation into Cancer and Nutrition (31), while it was significantly increased in the present study (HR = 1.48, 95 percent CI: 1.11, 1.97). The association between alcohol drinking and colorectal cancer or colon cancer appears to be stronger in Japanese populations than in Western populations.


Figure 1
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  		FIGURE 1. Hazard ratios for colorectal cancer by alcohol intake in Japanese (solid line) and Western (dashed line) populations. The solid line shows results for Japanese men from the present pooled analysis of five cohort studies (16–19); the dashed line shows results for Western men from a previous pooled analysis of eight cohort studies (22). The midpoint (mean) of the interval was assigned to each category of alcohol intake except the highest one (≥45 g/day), to which a value of 60 was assigned. Bars, 95% confidence interval.

 
If there is a difference in the magnitude of the association between alcohol drinking and risk of colorectal cancer, especially colon cancer, between Japanese and Western populations, what are the plausible explanations? Japanese have a high prevalence of the slow-metabolizing variant of the aldehyde dehydrogenase gene (8). The variant induces increased and persisting blood levels of acetaldehyde after alcohol ingestion (10). The modifying effect of the aldehyde dehydrogenase variant on the association between alcohol drinking and colorectal cancer risk was suggested in an earlier Japanese study (32); however, it has recently been challenged by large-scale studies (33, 34). Therefore, it remains unclear whether the seemingly stronger association among Japanese is explained by a genetic difference in the efficiency of metabolizing alcohol among regular drinkers. Alternatively, the clearer contrast in risk between drinkers and nondrinkers in Japanese may be ascribed to more precise classification of the nonexposure reference group, which presumably included a higher proportion of lifetime abstainers who were genetically unable to metabolize acetaldehyde.

Nongenetic factors may contribute to the heterogeneity in risk among populations. Folate deficiency is hypothesized to enhance the adverse effect of alcohol (35), and if Japanese alcohol drinkers have a higher prevalence of folate deficiency than their Western counterparts, a stronger association may emerge. However, in the present study as well as the pooled analysis of Western studies (22), there was only limited evidence suggesting a modifying effect of dietary folate on the alcohol-colorectal cancer association. Thus, folate probably does not explain the difference in the strength of association between the Japanese and Western studies. Instead, we found a pronounced association with alcohol intake in men with the lowest body mass indices, a finding compatible with results from the pooled analysis of Western studies (22).

This differential association by body composition has been interpreted on the basis of the insulin hypothesis: Alcohol drinking improves insulin resistance (36), which is increased in obese people (37) and may be related to increased risk of colorectal cancer (38) or colon cancer (39); thus, the carcinogenic potential of alcohol could be partially cancelled through its favorable effects on insulin resistance among obese persons. However, such a favorable action of alcohol may not benefit lean persons, whose risk of developing cancer through an insulin-mediated pathway may be minimal. The apparently stronger alcohol-colorectal cancer association in Japanese is thus attributable, at least in part, to their lower body mass index relative to that of Westerners. Nevertheless, our finding for obese men, showing a significant increase in risk with alcohol intake—a finding that was not observed in the pooled analysis among Western populations (22)—suggests that other characteristics of Japanese may intensify the effects of alcohol in colorectal carcinogenesis.

We also found a significant association with an alcohol intake of ≥23 g/day in women. Although the data did not allow us to assess risk for specific categories of greater alcohol intake, the hazard ratio associated with a 15-g/day increase in alcohol consumption in women was comparable to that for men (HRs were 1.13 for women and 1.11 for men). As previously suggested (22, 31), the effects of alcohol drinking on colorectal cancer risk may be similar in magnitude for men and women.

There were several strengths in the present study. First, we analyzed data from cohort studies that used validated questionnaires to collect data on alcohol consumption. Second, each study controlled for a common set of variables that are known or suggested to cause or prevent colorectal cancer, and all investigators confirmed that additional adjustment for physical activity did not alter their results. Third, with a large number of habitual drinkers in men, we were able to examine the risk of moderate drinking with reasonable statistical power. This point should be important from a public-health point of view; even a small increase in risk for an exposure category with a large number of drinkers leads to a considerable increase in the total number of cases, as for the present case in men (but not in women). Lastly, we estimated hazard ratios with and without exclusion of ex-drinkers from the reference category, by which we could infer the influence of ex-drinking on the association between alcohol drinking and colorectal cancer.

Our study also had some limitations. First, we used only baseline information on alcohol drinking, and thus we could not assess the effects of lifetime alcohol consumption or changes in drinking habits during follow-up on colorectal cancer risk. Second, random variation related to exposure measurement might have attenuated the associations. Third, although investigators in each study adjusted their results extensively for factors associated with colorectal cancer risk, we cannot exclude the possibility that our estimates were distorted because of residual confounding.

In summary, this pooled analysis of data from large prospective studies carried out in Japan confirmed that alcohol drinking is associated with increased risk of colorectal cancer in a dose-response manner in men and women. Although moderate drinking is associated with decreased risk of overall mortality (40), the present finding in men, showing a statistically significant 42 percent increase in colorectal cancer risk with an alcohol intake of 23–45.9 g/day, calls for attention. If the present association is causal, one fourth of all cases of colorectal cancer among Japanese men are attributable to an alcohol intake of ≥23 g/day. Moderation of alcohol drinking is an important aspect of the prevention of colorectal cancer. Further research is required to elucidate the roles of genetic and environmental factors that modify the alcohol-colorectal cancer association.


   ACKNOWLEDGMENTS
 
This work was supported by a grant (Third Term Comprehensive 10-Year Strategy for Cancer Control) from the Ministry of Health, Labour and Welfare, Japan.

The authors gratefully acknowledge the assistance of Izumi Suenega and Kie Nagao.

Members of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan: National Cancer Center, Tokyo—Shoichiro Tsugane (Principal Investigator), Manami Inoue, Shizuka Sasazuki, Motoki Iwasaki, Tetsuya Otani (until 2006), Norie Kurahashi (since 2007), and Taichi Shimazu (since 2007); Tohoku University, Sendai—Ichiro Tsuji (since 2004) and Yoshitaka Tsubono (in 2003); Miyagi Cancer Research Institute, Miyagi—Yoshikazu Nishino; Nagoya University, Nagoya—Kenji Wakai; Aichi Cancer Center, Nagoya—Keitaro Matsuo (since 2006); Gifu University, Gifu—Chisato Nagata; International Medical Center of Japan, Tokyo—Tetsuya Mizoue; Saga University, Saga—Keitaro Tanaka.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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