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Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1009-1013, May 2006
© 2006 American Association for Cancer Research

Alcohol Dehydrogenase 2 His47Arg Polymorphism Influences Drinking Habit Independently of Aldehyde Dehydrogenase 2 Glu487Lys Polymorphism: Analysis of 2,299 Japanese Subjects

Keitaro Matsuo, Kenji Wakai, Kaoru Hirose, Hidemi Ito, Toshiko Saito and Kazuo Tajima

Division of Epidemiology and Prevention, Aichi Cancer Center, Research Institute, Nagoya, Japan

Requests for reprints: 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
 
Although the functional effect of alcohol dehydrogenase 2 (ADH2) His47Arg polymorphism has been elucidated, its effect on habitual drinking remains unknown. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese subjects (989 men and 1,310 women). Drinking status, ethanol consumption, and physical reaction to one glass of beer were examined with regard to ADH2 and aldehyde dehydrogenase 2 (ALDH2) polymorphism. Strength of associations were assessed by age-, sex-, smoking status-, and genotype-adjusted odds ratios and their 95% confidence intervals. ADH2 His/Arg and Arg/Arg genotypes showed higher risk for habitual drinking. Among men, ALDH2 genotype- and confounder-adjusted odds ratios (95% confidence intervals) were 1.30 (0.89-1.89) and 3.16 (1.03-9.70), and this trend was significant (P = 0.024). A similar trend was observed among women. The combination genotypes of two polymorphisms revealed the clear effect of the ADH2 Arg allele among those with ALDH2 Glu/Lys in both sexes (Ptrend = 0.007 for men and 0.024 for women). Physical reactions, such as flushing and palpitation, were significantly less common in those with Arg/Arg compared with other ADH2 genotypes, and this was marked when combined with ALDH2 Glu/Lys. Heavy drinker status was also strongly associated with ADH2 Arg alleles. In conclusion, this study showed the strong effect of ADH2 His47Arg polymorphism on habitual drinking regardless of ALDH2 genotype. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1009–13)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Alcohol drinking is one of the most important modifiable lifestyle factors in a range of diseases, including cancer. Identification of factors that predispose to habitual drinking is therefore an important factor in the development of strategies for preventive lifestyle modification.

Alcohol is oxidized to acetaldehyde by the alcohol dehydrogenase (ADH) enzymes, especially by ADH2 and (formally ADH1B) enzyme. Acetaldehyde is further oxidized into acetate by the aldehyde dehydrogenase (ALDH) enzymes, and this oxidation is largely dependent on ALDH2 enzyme. The genes, which encode these two representative alcohol-metabolizing enzymes, display polymorphisms that modulate individual differences in alcohol- and acetaldehyde-oxidizing capacity (1-3). For ADH2, ADH2 Arg47His (the His allele) represents a superactive subunit of ADH2, which confers an ~40 times greater Vmax than the less active ADH2 Arg/Arg form of ADH2 (1, 4). The ALDH2 Glu487Lys polymorphism (the 487Lys allele), in contrast, has a catalytically inactive subunit (1, 4). Individuals with the ALDH2 Glu/Lys genotype have only 6.25% of the normal ALDH2 487Glu protein, indicating the dominant effect of the ALDH2 487Lys allele (5). The ADH2 47His and ALDH2 487Lys alleles, both of which lead to high acetaldehyde concentrations, are clustered in east Asian populations such as Japanese (6-8). Although several studies have investigated the significance of ALDH2 and ADH2 on drinking behavior, the effect of ADH2 polymorphism has never been clearly determined unlike that of ALDH2 polymorphism (reviewed in ref. 9). Further, considering the biological effect of these polymorphisms, a combined effect might also be expected, but this also has not been elucidated.

Here, to clarify the effect of ADH2 polymorphism alone and that of the combination of ADH2 and ALDH2 polymorphisms on drinking behavior, we investigated the influence of these factors on drinking behavior in 2,299 nonalcoholic subjects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Subjects were 2,299 noncancer and nonalcoholic outpatients (989 men and 1,310 women) who first visited Aichi Cancer Center Hospital between January 2001 and August 2004. Confirmation of noncancer status was done using hospital-based cancer registries, whereas a history of cancer or alcoholism was based on self-reports. All subjects were recruited in the framework of the Hospital-Based Epidemiologic Research Program at Aichi Cancer Center described in detail elsewhere (10-12). Briefly, all first-visit outpatients are asked to fill out a questionnaire regarding lifestyle and to provide a 7-mL sample of blood. Approximately 95% of eligible subjects completed the questionnaire and 50% provided blood. We confirmed previously that lifestyle patterns of first-visit outpatients are accordant with those in a general population randomly selected from Nagoya City (13). This study was approved by the Ethics Committee of Aichi Cancer Center.

Genotyping of ALDH2 and ADH2
DNA of each subject was extracted from the buffy coat fraction with a BioRobot EZ1 and EZ1 DNA Blood 350 µL kit (Qiagen K.K., Tokyo, Japan). Genotyping was based on duplex PCR with the confronting two-pair primer method as described elsewhere (7). Genotypes were confirmed with Taqman Assays by Applied Biosystems (Foster City, CA).

Alcohol Consumption and Physical Reaction to Alcohol
Information related to alcohol consumption was obtained via the self-administered questionnaire, which asked questions on drinking status (never, former, and current) as well as frequency and dose, age at starting habitual drinking, and physical reaction to one glass of beer. Reactions categories included flushing, palpitations, nausea, headache, drowsiness, breathlessness, and discomfort in the three levels of never, occasional, and usual. Alcohol consumption of each type of beverage (Japanese sake, beer, shochu, whiskey, and wine) was determined from average number of drinks per day, which was then converted into a Japanese sake (rice wine) equivalent. Total alcohol consumption was estimated as the summed amount of pure alcohol consumption (grams per drinking session) of Japanese sake, beer, shochu, whiskey, and wine among current and former regular drinkers. Information on smoking status was obtained in the three categories of nonsmoker, former smoker, and current smoker.

Statistical Analysis
All statistical analyses were done using Stata version 8 (Stata Corp., College Station, TX). Ps < 0.05 were considered significant. The {chi}2 test was applied to examine frequencies of certain factors across genotypes. The nonparametric Kruskal-Wallis test was applied to assess continuous variables in relation to genotypes. Alcohol exposure was categorized in two ways: (a) drinking status: never drinkers, former drinkers, and current drinkers (based on self-reports) and (b) ethanol consumption: level 1 (0 g/d), level 2 (between >0 and ≤25 g/d), level 3 (between >25 and ≤50 g/d), and level 4 (>50 g/d). Unconditional logistic regression was employed to calculate odds ratios (OR) and their 95% confidence intervals (95% CI) for drinking level status. Comparisons were made in three ways: (a) current and former drinkers versus never drinkers, (b) high-level drinkers (level 4) versus low- and moderate-level drinkers (levels 2 and 3), and (c) high-level drinkers (level 4) versus low-level drinkers (level 2). Each OR was estimated for ADH2 and ALDH2 genotypes and their combination. Potential confounders considered in the multivariate analyses were age, sex, and smoking. Accordance with the Hardy-Weinberg equilibrium was confirmed for all subjects with the {chi}2 test to assess any discrepancies between the observed and the expected genotype frequencies based on the allele frequencies observed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Genotype distributions according to age and drinking/smoking status are shown in Table 1 . In total, ALDH2 Glu487Lys genotype frequencies were 49.6% (Glu/Glu), 40.9% (Glu/Lys), and 9.4% (Lys/Lys). Allele frequency for the Lys allele was 0.30 and genotype distribution was accordant with the Hardy-Weinberg equilibrium (P = 0.26). Genotype distribution of the ADH2 His47Arg polymorphism was as follows: 61.4% (His/His), 33.7% (His/Arg), and 4.9% (Arg/Arg). Allele frequency for the His allele was 0.70 and distribution was accordant with the Hardy-Weinberg equilibrium (P = 0.62). There were no statistically significant differences in ADH2 genotype distribution according to sex, age, drinking status, or smoking status, although current drinkers were more prevalent among the ADH2 Arg/Arg genotype than the others. The distribution of ALDH2 genotypes significantly differed according to drinking status, as expected, and according to age and smoking status, although only marginally. Men were more likely to be current drinkers. Based on these results, we decided to stratify all analyses by sex and include age and smoking as confounders. The distribution of the combination of ADH2 and ALDH2 polymorphisms is presented in Table 2 .


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  		Table 1. Characteristics of subjects

 

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  		Table 2. Combined genotypes distribution of ADH2 and ALDH2

 
Table 3 shows the distribution of genotypes for ADH2 and ALDH2 and never versus ever drinking status. The ALDH2 Lys/Lys genotype was consistently associated with refrain from drinking. The adjusted ORs (95% CIs) for ever drinkers among men were 0.12 (0.08-0.18) and 0.004 (0.002-0.01) for the ALDH2 Glu/Lys and Lys/Lys genotypes, respectively, relative to the Glu/Glu genotype (Ptrend < 0.001). This was consistently observed in women also. Contrary to findings with the ALDH2 Lys allele, the ADH2 Arg allele showed an increasing trend toward ever drinkers. Men with the His/Arg and Arg/Arg genotypes showed adjusted ORs (95% CIs) of 1.30 (0.89-1.89) and 3.16 (1.03-9.70) relative to those with the His/His genotype, and this trend was statistically significant (P = 0.024). Women showed similar results. In addition, because these results were based on mutual adjustment of ALDH2 and ADH2 in the models, the ALDH2 and ADH2 genotypes were independent contributors to ever drinker status. Tests for interaction between ALDH2 and ADH2 genotypes to ever drinker status showed no statistical significance in either men or women.


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  		Table 3. Combined genotype of ADH2 and ALDH2 and ORs (95% CIs) for being ever drinkers

 
Table 4 shows the combined effect of ALDH2 and ADH2 genotypes according to sex. As expected from the results in Table 1, the ALDH2 genotype showed a decreasing trend to ever drinker status regardless of ADH2 genotype. Ptrends consistently showed statistical significance. In contrast, although ADH2 genotypes consistently showed an increasing trend to ever drinker status, their effect was evidently seen only in those with the ALDH2 Glu/Lys genotype. Ptrends were significant in both men (Ptrend = 0.007) and women (Ptrend = 0.024).


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  		Table 4. Combined genotype of ADH2 and ALDH2 and ORs (95% CIs) for being ever drinkers

 
Table 5 shows median ethanol consumption per day according to sex and ALDH2 and ADH2 genotype among ever drinkers. An increased number of Lys alleles in ALDH2 polymorphism clearly correlated with decreased ethanol consumption in both sexes. The Arg allele of ADH2 seemed to have at least some effect on ethanol consumption, although statistical significance was observed only among men (P = 0.0003) with the Kruskal-Wallis test. A consistent trend was observed when combined genotypes of ADH2 and ALDH2 were examined. Trend and significance were not changed when the analyses were limited to current drinkers (data not shown). Table 6 shows the association between combined ALDH2 and ADH2 genotypes and physical reactions to low alcohol consumption. The effect of the ALDH2 genotypes seemed evident in all reactions, whereas that of ADH2 was also evident in reactions, such as skin rash and palpitation, and magnitude was greater in those harboring the ALDH2 Lys allele.


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  		Table 5. Average ethanol consumption and age at start drinking among ever drinkers

 

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  		Table 6. Physical reaction to small amount of ethanol exposure

 
The effect of the combined ALDH2 and ADH2 genotypes on ever drinker status is assessed in Table 4. We further examined the effect of ADH2 and ALDH2 genotypes on being heavy drinkers (consumption of >50 g ethanol/d; level 4). When levels 2 and 3 drinkers were defined as the reference, ADH2 His/Arg and Arg/Arg showed significantly higher adjusted ORs (95% CIs) for level 4 drinker status [i.e., 1.98 (1.18-3.32) and 2.87 (1.14-7.25), respectively] relative to His/His among men. The adjusted OR for the ALDH2 Glu/Lys genotype relative to Glu/Glu was significantly lower than unity. No level 4 drinker in men was ALDH2 Lys/Lys. Among women, only the ADH2 Arg/Arg genotype showed a significantly high OR (95% CI) at 4.98 (1.57-15.8). The adjusted OR for His/Arg was similar to that for His/His. In contrast to that with men, the adjusted OR for women with ALDH2 Glu/Lys was not significantly lower than unity. When all genotype combinations were examined, these observed trends were consistent. Moreover, all the above trends were consistently observed when the comparison was made between levels 4 and 2 drinkers.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study in >2,000 Japanese subjects identified strong associations between ADH2 polymorphisms and drinking behavior regardless of ALDH2 polymorphism.

An increase in the ADH2 Arg allele was a significant risk factor for habitual drinking, especially in men. Ethanol consumption among men was significantly greater in those harboring the ADH2 Arg allele. The risk of heavier drinker was also affected by the this allele. A lower frequency of adverse physical reactions in those having more Arg alleles was consistently observed. These observations are biologically plausible when the slower acetaldehyde generating activity of the ADH2 Arg allele is considered. One notable finding is that the effect of the Arg allele on heavier drinkers was allele dose dependent in men, whereas it was evident only in subjects having the Arg/Arg genotype in women. As drinking behavior is strongly influence by social factors, including sexual differences, such observation of sex-dependent differences seems reasonable.

A second important finding was the combination effect of ADH2 and ALDH2 polymorphisms. We found that the ADH2 Arg allele had a greater effect on habitual drinking among those with the ALDH2 Glu/Lys than the other ALDH2 genotypes. This finding was consistent between sexes. Considering the slower oxidation activity with the Arg allele, this linear effect of the Arg alleles for those with somewhat reduced ALDH2 activity is reasonable. Relatively delayed production of acetaldehyde by the ADH2 Arg allele compared with the His allele allows individuals to metabolize acetaldehyde in spite of the reduced oxidation activity of ALDH2. Our observation regarding ADH2 polymorphism is inconsistent with previous reports describing a lack of effect of ADH2 polymorphism on drinking habit (14). This dissociation might be due to a lack of power in the design associated with the partitioning of subjects into nine groups. Tight linkage between ADH2 and ADH3 polymorphisms has been reported (15) and the effect of ADH3 polymorphism remains to be elucidated. In addition, Yamamoto et al. reported a lack of association between blood acetaldehyde concentration and ADH2 polymorphism (16). This latter finding requires further consideration before the role of ADH2 polymorphism in drinking behavior can be conclusively determined.

The ALDH2 Lys/Lys genotype showed a strong association with nondrinking. This finding is completely consistent with previous studies. The effect of ADH2 genotype in this subpopulation seemed consistent, as it was also observed with the ALDH2 Glu/Lys type; however, the limited number of drinkers in this subpopulation limits its interpretability.

Several methodologic issues in the present study warrant consideration. A limitation may be the base population, which composed of noncancer and nonalcoholic patients at the Aichi Cancer Center Hospital. However, as we applied a common framework to subject enrollment regardless of drinking status or ADH2/ALDH2 genotype, we consider this comparison of subjects according to drinking status to be reasonable. In addition, a notable point of our control population is its similarity to the general population in terms of the exposures of interest (i.e., smoking and drinking; ref. 13). This may confirm the external validity to the general population, assuming that consent to blood sampling is not influence by ADH2 and ALDH2 genotype. A strength of the study may be the similarity in genotype distributions for the ADH2 His47Arg and ALDH2 Glu487Lys polymorphisms between our controls and the general population (17). The medical background of the controls is another potential source of bias; however, our previous study showed only a limited effect for this variable (18). It is difficult to rule out the possible contamination of alcoholic subjects because alcoholic information was based on self-reporting. Finally, as we did not adjust Ps in consideration of the multiple comparison issue, it is difficult to state that the chance effect did not influence the results. Careful interpretation is required.

In conclusion, our study revealed the significant effect of ADH2 His47Arg polymorphism on drinking behavior regardless of the presence of ALDH2 Glu487Lys polymorphisms in a large Japanese population.


   Footnotes
 
Grant support: Grant-in Aid for Scientific Research on Cancer Epidemiology in a Special Priority Area (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan and Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/30/05; revised 2/ 8/06; accepted 2/23/06.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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