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Carcinogenesis Advance Access originally published online on December 6, 2005
Carcinogenesis 2006 27(5):1018-1023; doi:10.1093/carcin/bgi282
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A gene–gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan

Keitaro Matsuo 1, *, Kenji Wakai 1, Kaoru Hirose 1, Hidemi Ito 1, Toshiko Saito 1, Takeshi Suzuki 1, 4, Tomoyuki Kato 2, Takashi Hirai 2, Yukihide Kanemitsu 2, Hiroshi Hamajima 3 and Kazuo Tajima 1

1 Division of Epidemiology and Prevention, 2 Department of Gastroenterological Surgery and 3 Department of Clinical Laboratory, Aichi Cancer Center, Nagoya, Japan and 4 Department of Internal Medicine and Molecular Science, University Graduate School of Medical Science, Nagoya City, Japan

* To whom correspondence should be addressed at: Keitaro Matsuo, Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Fax: +81 52 763 5233; E-mail: kmatsuo{at}aichi-cc.jp


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Alcohol consumption is recognized as a potential risk factor for colorectal cancer (CRC). Genetic polymorphisms, aldehyde dehydrogenase (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in Japanese population but their significance for CRC carcinogenesis remains to be clarified in detail. We, therefore, conducted a matched case–control study with 257 incident CRC cases and 771 non-cancer controls at Aichi Cancer Center, including analysis of interactions between polymorphisms, drinking and folate consumption. The ADH2 Arg allele was found to be associated with increased risk, the odds ratios (ORs) being 1.35 (95% confidence interval: 1.00–1.84) and 1.93 (1.06–3.53) for the His/Arg and Arg/Arg genotypes, respectively. In contrast, no apparent links were observed with the ALDH2 genotypes. Individuals having ALDH2 Glu/Glu with ADH2 Arg+, ALDH2 Lys+ with ADH2 His/His and ALDH2 Lys+ with ADH2 Arg+ showed ORs of 0.10(0.04–0.21), 0.10 (0.06–0.19) and 1.36 (0.94–1.97), respectively, compared with ALDH2 Glu/Glu with ADH2 His/His. Statistical gene–gene interaction was significant between the two polymorphisms for the risk of CRC (P< 0.001). The impact of ALDH2 Lys+ with ADH2 Arg+ was more evident in low folate consumer (OR = 2.32, 1.19–4.55) than high folate consumer (OR 1.38, 0.80–2.38). In conclusion, while we failed to find any significant association with the ALDH2 polymorphism itself, significant interaction between ALDH2 and ADH2 polymorphism was observed. Replication in the future study is warranted.

Abbreviations: ACCH, Aichi Cancer Center Hospital; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; BMI, Body-mass index; CIs, confidence intervals; CRC, colorectal cancer; HRT, hormone-replacement therapy; ORs, odds ratios


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Colorectal cancer (CRC) has long been one of the common sites of cancer development in Western countries, and is rapidly increasing in Japan (1). Recently, the age-adjusted incidence rates for males were 44.4 and 49.3 and those for females were 26.5 and 32.8 in Northern America and Japan, respectively (2). Several epidemiological studies conducted in Japan showed that there was increased risk of CRC for alcohol drinkers (3–5). Parallel increase in the incidence of CRC and alcohol consumption in Japan (6) along with epidemiological findings gives strong support for alcohol drinking as one of the important risk factors among Japanese population. This is consistent with the findings of epidemiological studies in other countries (7,8). The background mechanisms underlying the impact of alcohol on the colon have been extensively studied; however, many areas remain unclear. One hypothesis involves interference with one-carbon metabolism by alcohol or its metabolite, acetaldehyde. Folate, one of the main micronutrient in the one-carbon metabolism, is considered as the potential protective factors for CRC. Several studies suggested interaction between this nutrient and alcohol consumption (9). Another possibility is that acetaldehyde induces direct and indirect genotoxic effect (10,11).

Alcohol is oxidized to acetaldehyde by the alcohol dehydrogenase (ADH) enzymes, especially by ADH2. Acetaldehyde is further oxidized into acetate by aldehyde dehydrogense enzymes (ALDHs), and this oxidation owes much to ALDH2. Encoding genes for these two representative alcohol-metabolizing enzymes display polymorphisms that modulate individual differences in alcohol-oxidizing capability and drinking behavior (12–14). Regarding ADH2 Arg47His, the 47His allele represents a superactive subunit of ADH2 that has about 40 times higher Vmax than the less active ADH2 Arg/Arg form of ADH2 (12,15). As for the ALDH2 Glu487Lys polymorphism, the 487Lys allele encodes a catalytically inactive subunit (12,15). Individuals with the ALDH2 Glu/Lys genotype have only 6.25% of normal ALDH2 487Glu protein; indicating a dominant effect of ALDH2 487Lys (16). The ADH2 47His and ALDH2 487Lys alleles, both leading to high acetaldehyde concentrations, are clustered in east Asian populations such as the Japanese (17–19). Therefore, these two genetic polymorphisms modify the drinking habit (20) and are expected to affect CRC risk, especially in Asian populations whose frequencies for minor alleles are common. However, scarce evidence is available for the combined impact of ADH2 and ALDH2 polymorphisms on CRC risk by alcohol drinking.

The primary aim of this case–control study is to clarify the impact of ADH2 and ALDH2 polymorphisms on CRC risk. The interactions between two polymorphisms as well as between polymorphisms and alcohol and folate consumption were also evaluated.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Subjects
Cases were 257 patients who were histologically diagnosed as having CRCs (123 colon cancers, 131 rectal cancers and 3 CRCs) between January 2001 and August 2004 at Aichi Cancer Center Hospital (ACCH) and did not have any prior history of cancer as described elsewhere (21). Controls were first visit outpatients who had visited ACCH during the same period and were confirmed to have no cancer and no prior history of neoplasia. Controls were randomly selected and matched for age (±3 years) and sex to cases with a 1:3 case–control ratio (n = 771) to achieve more than 80% power to detect an OR of 2.0 with the proportion of the risk genotype among controls being 40%. The subjects were selected from the database of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

The framework of HERPACC has been described elsewhere (22–24). Briefly, all first visit outpatients, aged 20–79 years, were asked to fill out a questionnaire regarding their lifestyle as well as to provide 7 ml of blood. Approximately 95% of eligible subjects completed the questionnaire and 55% provided blood samples. Approximately 30% of first visit outpatients were diagnosed as having cancer at ACCH. Under the assumption that the non-cancer population within HERPACC will visit ACCH when they suffer from cancer in the future, we define non-cancer first visit outpatients as the population where cases may arise. Our previous study showed lifestyle patterns of first visit outpatients to be in accordance with those in the general population randomly selected from the Nagoya city, confirming external validity for the study (25). Written informed consent was obtained from all the subjects and this investigation was approved by the ethical committee of ACC.

Genotyping of ALDH and ADH
DNA of each subject was extracted from the buffy coat fraction with BioRobot EZ1 and EZ1 DNA Blood 350 µl Kits (Qiagen K.K., Tokyo, Japan). Genotyping was based upon duplex PCRs with the confronting two-pair-primer (PCR-CTPP) method (18). Briefly, four primers for the ADH2 polymorphism (F1ADH2, 5'-GGGCTTTAGACTGAATAACCTTGG-3'; R1ADH2, 5'-AACCACGTGGTCATCTGTGC-3'; F2ADH2, 5'-GGTGGCTGTAGGAATCTGTCA-5'; R2ADH2, 5'-AGGGAAAGAGGAAACTCCTGAA-3') and four primers for the ALDH2 polymorphism (F1ALDH2, 5'-TGCTATGATGTGTTTGGAGCC-3'; R1ALDH2, 5'-CCCACACTCACAGTTTTCACTTC-3'; F2ALDH2, 5'-GGGCTGCAGGCATACACTA-3'; R2ALDH2, 5'-GGCTCCGAGCCACCA-3') were mixed in a 25 µl volume with 0.18 mM dNTPs, 0.5 U of AmpliTaq Gold DNA polymerase (Perkin-Elmer, Foster City, CA), and 2.5 µl x 10 PCR buffer including 15 mM MgCl2. PCR conditions were as follows: 10 min of initial denaturation at 95°C, followed by 40 cycles of 1 min at 95°C, 1 min at 63°C and 1 min at 72°C with 5 min of final extension at 72°C. The results were confirmed by the PCR restriction fragment length polymorphism method using MslI (New England BioLab, MA) for both polymorphisms.

Quality of genotyping was routinely assessed statistically using the Hardy–Weinberg test in our laboratory. When allelic distributions for controls departed from the Hardy–Weinberg frequency, genotyping was assessed using another method. Identification was double-blind checked, and the results of genotyping were loaded into a computer by two separate data managers independently.

Assessment of folate and alcohol intake
Dietary folate intake was assessed with a semi-quantitative food frequency questionnaire (SQFFQ), which included 47 foods or dishes. The approach for developing the SQFFQ and computing the nutrient intake are described elsewhere (26–28). Briefly, folate intake was computed by multiplying the frequency of food intake, the serving size (in grams) and the folate content (per 100 g) of food as listed in the Standard Tables of Food Composition and the Follow-up of the Standard Tables of Food Composition (29), and then the sum from the various foods or dishes was calculated as the total folate intake. In the validation study of SQFFQ, the deattenuated, log-transformed and energy-adjusted Pearson's correlation coefficients for folate between SQFFQ and that in three-day weighted dietary records were 0.36 for males and 0.38 for females (28).

Alcohol consumption of each type of beverage (Japanese sake, beer, shochu, whiskey and wine) was determined with respect to the average number of drinks per day, which was then converted into a Japanese sake (rice wine) equivalent. One Japanese drink equates to one ‘go’ (180 ml) of Japanese sake which contains 25 g of ethanol, one large bottle (720 ml) of beer, two shots (57 ml) of whiskey or two-and-a-half glasses of wine (200 ml). One drink of ‘Shochu’ (distilled spirit) which contains 25% ethanol was rated as 108 ml. Total amount of alcohol consumption was estimated as the total sum of pure alcohol consumption (gram per consumption) of Japanese sake, beer, shochu, whiskey and wine among current and former regular drinkers.

Statistical analysis
Statistical analyses were performed using Stata version 8 (Stata, College Station, TX). P-value < 0.05 was considered statistically significant, and adjustment by multiple comparisons was not performed because of the exploratory setting of the study. Conditional logistic regression models were employed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of CRC. Interaction between two ADH2 and ALDH2 were assessed by including scores of these polymorphisms (ADH2 His/His: 0, Arg+: 1, ALDH2 Glu/Glu: 0, Lys+: 1) and cross product of the scores. Alcohol exposure was categorized into three levels, non-drinker (never drinker), moderate drinker and heavy drinker. Heavy drinkers were defined as those who drank alcoholic beverage 5 days or more per week with an amount of 50 g or more ethanol on each occasion, while moderate drinkers were defined as those other than heavy drinkers. Smoking status was also divided into three categories considering cumulative exposure to tobacco: non-smokers (never smokers), smokers with pack-years (PY) equal to or less than 20 (moderate smokers) and smokers with a PY more than 20 (heavy smokers). Energy adjusted daily folate consumption was categorized into two groups by quartile (Q1, and Q2–Q4) under the assumption that the lowest consumption leads to the highest risk. Potential confounders considered in the multivariate analyses were age, sex, referral pattern to ACCH, body-mass index (BMI), past usage of hormone-replacement therapy (HRT), current or past medical history and a family history of CRC. Family history of CRC was defined as a positive CRC in parents and/or siblings. HRT history was defined as positive when subjects had received any type of hormonal therapy including fertilization treatment, post-oophorectomy and post-menopause. Current or past medical history was considered for the diseases assumed to be associated with non-steroidal anti-inflammatory drug (NSAID) usage such as cardiovascular diseases, cerebrovascular diseases and rheumatoid diseases. Accordance with the Hardy–Weinberg equilibrium was checked for controls with the {chi}2 test and exact P-values were used to assess any discrepancies between expected and observed genotype and allele frequencies. Trend of genotype was assessed by score test applying score for each genotypes (0, homozygous for reference allele; 1, heterozygote; and 2, homozygous non-reference allele).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Table I shows baseline characteristics for the total of 257 CRC cases, with an average age of 58.8 years, and the 771 controls, matched with reference to sex and age. Males accounted for 63.0% of the studied subjects. Neither the drinking nor the smoking status significantly differed between the two groups. The level of cumulative exposure to smoking was also similarly distributed between the two groups. Energy adjusted daily folate consumption was slightly higher among controls, though this was not significant and BMI values also did not differ. Only the family history of CRC was significantly more common in cases (P = 0.038). There were no differences between colon and rectal cancers (data not shown).


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  		Table I. Characteristics of cases and controls

 
Table II shows genotype distributions for ADH2 and ALDH2 and combination, and their ORs and 95% CIs for CRC. The genotype frequencies for all the polymorphisms were in accordance with the Hardy–Weinberg equilibrium in controls and allele frequencies were also quite in accordance with earlier reports in Japan (30). The frequencies of the His/His, His/Arg and Arg/Arg (ADH2 His47Arg) were 61.6, 33.7 and 4.7% among controls and 52.9, 39.7 and 7.4% among cases, respectively. Significantly increased risk of CRC was observed with His/Arg and Arg/Arg relative to His/His (1.39, 95% CI: 1.02–1.87; 1.92 95% CI: 1.06–3.46; trend = 0.006 for Model 1). The frequencies of the Glu/Glu, Glu/Lys and Lys/Lys of ALDH2 Glu487Lys polymorphism were 49.9, 40.9 and 9.2% among controls and 50.2, 40.5 and 9.3% among cases, and no significant elevation of risk was observed with the ALDH2 genotype alone. In the analysis for combination, compared with subjects having ALDH2 Glu/Glu with ADH2 His/His, age–sex-adjusted ORs and 95% CIs for those with ALDH2 Glu/Glu and ADH2 Arg+, ALDH2 Lys+ and ADH2 His/His, and ALDH2 Lys+ and ADH2 Arg+ were, 0.10 (0.05–0.22), 0.12 (0.07–0.22), and 1.48 (1.07–2.06), respectively. A model including confounders showed similar association.


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  		Table II. Genotype distributions of ADH2 and ALDH2 polymorphisms

 
In Table III, the impact of combined genotypes on CRC risk stratified by alcohol drinking is presented as ORs adjusted for age, sex, BMI, family history, medical history, HRT history, and smoking and drinking status. The ORs for each combination within non-drinkers and moderate drinkers showed consistent result as those in all subject analysis. Statistically significant interaction between ADH2 and ALDH2 genotypes for CRC risk was observed in analyses for all subjects and moderated drinkers (P< 0.001 for both).


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  		Table III. Genotype distribution of ADH2/ALDH2 according to drinking status and their ORs for CRC Risk

 
Impact of folate consumption was assessed. The adjusted ORs for the Q2, Q3 and Q4 relative to Q1, the lowest consumption were 0.81 (0.54–1.21), 0.72 (0.48–1.09) and 0.97 (0.65–1.44), respectively. Although it did not show statistically significant risk change by itself, adjusted OR for Q2–Q4 combined was 0.83 (0.60–1.4) relative to Q1 group indicating higher consumption may decrease CRC risk. Further examination of the impact of the combined genotypes according to folate and alcohol consumption are presented in Table IV. In the overall analysis, ORs and 95% CIs for those with ALDH2 Lys+ and ADH2 His/His, and those with ALDH2 Glu/Glu and ADH2 Arg+, were consistent across folate consumption levels. In contrast, the ORs were higher in those with lower intake level than in those with higher intake, among subjects with ALDH2 Lys+ and ADH2 Arg. The impact of genotype ADH2 Arg+ and ALDH2 Lys+ seemed to be enhanced within those who consume more alcohol with low folate consumption. Such association was not evident in the analysis for folate among Q2–Q4 subjects.


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  		Table IV. Impact of ADH2/ALDH2 genotypes stratified by folate and alchol consumption

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study demonstrated a significant gene–gene interaction between ADH2 His47Arg and ALDH2 Glu487Lys polymorphisms in relation to the risk of CRC, with ALDH2 Glu/Glu and ADH2 Arg+ or ALDH2 Lys+ and ADH2 His/His having the lowest risk. Of interest, this risk reduction was consistent across the drinking habit. In addition, the impact of combination of ADH2 Arg+ and ALDH2 Lys+ genotypes was more evident in low folate consumers compared with high consumers, indicating possible interaction between folate intake and the genotypes.

In this study, we indirectly evaluated the impact of acetaldehyde on CRC carcinogenesis by assessing the prevalence of polymorphisms highly associated with acetaldehyde metabolism. To the best of our knowledge, this is the first study to examine both ADH2 and ALDH2 polymorphisms with reference to CRC, one reason being the low allele frequencies for ALDH2 487Lys and ADH2 47His in populations other than the Japanese. Yokoyama et al. (31) first examined the association between ALDH2 Glu487Lys and colon cancer among Japanese alcoholics and reported a 3-fold increased risk among heterozygotes. Another study demonstrated a marginally significantly increased risk for colon but not rectal cancer for the ALDH2 Glu/Lys genotype (32). Our preliminary evaluation failed to find a significant association overall, but suggested an interaction between heavy drinking and ALDH2 genotype (33). These results motivated us to examine the possible role of ALDH2 polymorphism in CRC genesis under the assumption that acetaldehyde is carcinogenic. We set our study to detect increased CRC risk by ALDH2 487Lys alone with enough statistical power, so that the lack of association in this study is very significant.

The increased risk with the ADH2 Arg allele, despite no association with ALDH2, is also suggestive. The ADH2 enzyme converts alcohol to acetaldehyde and the 47Arg allele has relatively weak activity, suggesting that the elimination of alcohol rather than acetaldehyde is important for CRC carcinogenesis; however, analysis of ADH2 and ALDH2 genotypes in combination did not support this assumption. As shown in Table III, the low CRC risk groups were ALDH2 Glu/Glu with ADH2 Arg+ and ALDH2 Lys+ with ADH2 His/His, indicative of a strong interaction between these two polymorphisms. One of the surprising observations in this study was that the effects of genotypes were consistent even in non-drinkers. One interpretation is that a substrate other than alcohol/acetaldehyde exists which is metabolized by ADH2/ALDH2 enzymes. Alternatively, alcohol synthesis by colonic flora might play a role. Clarification of this point is required.

In this study, low folate consumption seemed to have increased risk of CRC, though it may not be significant. In the analysis considering genotype, low folate consumption had an enhanced impact (OR = 2.32) with the highest risk genotype, ADH2 Arg+ and ALDH2 Lys+. This appeared greater with moderate or high consumers of alcohol than with non-drinkers. Our results suggest combination of unfavorable conditions, heavier drinking, risk genotypes and low folate consumption might enhance the risk of CRC. Acetaldehyde is known to be able to cleave folate (34). In addition, ethanol reaching the large bowel mucosa, where the concentration may be equal to that in the blood stream (35), is converted to acetaldehyde by intestinal microorganisms (36) thus leading to depletion of folate in the mucosa. Bearing this in mind, it is reasonable to consider that functional genetic variation in enzymes responsible for alcohol metabolism interact with folate consumption as well as drinking itself.

Potential limitations of the present study must be considered. One methodological issue is selection of the base population for controls. We applied non-cancer patients at the ACCH for this purpose because it is reasonable to assume our cases arose within this population base. A notable point of our control population is its similarity to the general population in terms of exposures of interest, here alcohol drinking (25). The genotype distribution for the ALDH2 and ADH2 polymorphisms in our controls was similar to that in the general population (37). Medical background of controls is another potential source of bias; however, our previous study focusing on females demonstrated a limited impact. More than 66% of non-cancer outpatients at ACCH do not have any specific medical condition. The remaining 34% have specific diseases, such as benign tumors and/or non-neoplastic polyps (13.1%), mastitis (7.5%), digestive disease (4.1%) or benign gynecological disease (4.1%) (38). With men, the circumstance is similar. In addition, contrary to standard hospital-based studies, the HERPACC system is less prone to be affected by information bias because all data are collected prior to diagnosis. The limited number of cases is another factor and replication of our findings in a larger study is warranted.

In conclusion, the present case–control study showed a significant gene–gene interactions between ADH2 and ALDH2 polymorphisms regarding CRC risk in a Japanese population.


   Acknowledgments
 
The authors are grateful to Ms. Fujikura, Ms Fukaya, Ms Kamori, Ms Tomita, Ms Hattori, Ms Shimada, Ms Sato, Ms Yamauchi and Ms Yoshida for their help with the investigation. Hatsumi Achiwa, Takako Sato and Miki Watanabe are also greatly appreciated for their technical help with laboratory assays. The study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology of Japan and a Grant-in-Aid for the Third Term Comprehensive 10-Year-Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan.

Conflict of Interest Statement: None declared.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received September 12, 2005; revised October 19, 2005; accepted November 20, 2005.


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