Alcohol and Alcoholism Advance Access originally published online on January 23, 2008
Alcohol and Alcoholism 2008 43(2):143-147; doi:10.1093/alcalc/agm173
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Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers
Department of Environmental Health Sciences, Akita University School of Medicine, Akita City, Japan
* Author to whom correspondence should be addresses: Tel.: +81-18-884-6085; Fax: +81-18-836-2608; E-mail: winestem{at}med.akita-u.ac.jp
Received 24 August 2007; first review notified 5 October 2007; in revised form 27 October 2007; accepted 23 November 2007
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ABSTRACT |
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Aims: The objective was to clarify the effect of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) genotypes on the diabetic risk in Japanese workers. Methods: At the time of mandatory health checkup, the ADH2 and ALDH2 genotypes, as well as fasting plasma glucose (FPG) levels, body mass index (BMI), smoking habit, and weekly alcohol intake, were examined in 492 men and 183 women working at motor vehicle dealerships. Results: In using two-way analysis of variance to manipulate ADH2 and ALDH2 genotypes and alcohol intake (>70 g/week for men and >35 g/week for women), the FPG level after the adjustment for age, BMI, smoking habit, and another genotype was significantly higher in the men with ADH2*1/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH2*1/1 genotype. In contrast, the women with ALDH2*1/1 genotype had significantly lower FPG levels than those with the other genotypes, but there was no significant difference in the FPG level between the women with and without ADH2*1/1 genotype. Also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the women. Conclusions: These findings suggest that genotypes of ADH2 and ALDH2 can modify the diabetic risk, irrespective of amounts of alcohol consumed. Also, there may be sex differences in the effect of these enzyme genotypes on glucose metabolism.
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Introduction |
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The risk of developing type 2 diabetes increases with age and obesity, but the specific etiologies remain unknown (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003
). In Western countries, moderate alcohol intake has been considered to have a protective effect on diabetes (Howard et al., 2004; Carlsson et al., 2005; Koppes et al., 2005), whereas heavy alcohol intake should be associated with increased risk. On the other hand, Waki et al. (2005) have reported that moderate-to-high alcohol intake is positively associated with the incidence of type 2 diabetes in Japanese men with body mass index (BMI) of less than 22 kg/m2. The confusion of the causation between alcohol intake and diabetes may have been due to differences in the distribution of polymorphic ethanol-metabolizing enzymes, as well as in the BMI and lifestyles, between Western and Japanese populations. Therefore, it is necessary to ascertain a link between glucose metabolism and polymorphic enzymes such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), in relation to the amount of alcohol consumed.
Alcohol is oxidized to acetaldehyde by ADH (especially, ADH2) in the body. After that, acetaldehyde is oxidized to acetate by ALDHs, and this oxidation owes chiefly to ALDH2 (Matsuo et al., 2006). The mutant ADH2*2 allele encodes a superactive subunit of ADH2, and the Vmax of superactive ADH2*2 homodimers is about 40 times higher than that of the less active ADH2*1/1 form (Bosron and Li, 1986; Yokoyama et al., 2002). Also, the ALDH2*2 allele encoding the inactive form causes almost complete loss of catalytic activity (Crabb et al., 1989; Higuchi et al., 2004). Since the frequency of the Japanese population with the ADH2*2 or ALDH2*2 allele is relatively high as compared to the Caucasians, the alleles influence both health and drinking behaviour of the Japanese (Takeshita et al., 1994; Yokoyama and Omori, 2003; Higuchi et al., 2004). For instance, the ADH2*1 allele was found to be associated with a lower blood-insulin concentration in subjects consuming light or moderate amounts of alcohol (Suzuki et al., 2006) and habitual light-to-moderate alcohol intake was found to worsen glycemic control in diabetic patients who had the inactive ALDH2*2 allele (Murata et al., 2000); while, Beulens et al. (2007) reported that the ADH1C genotype modified the association between alcohol consumption and diabetes in Caucasians. Concerning the effect of alcohol intake on glucose metabolism, thus, these findings seem to highlight the importance of data analysis considering both genotypes as possible confounders.
Type 2 diabetes has been considered to be equally prevalent among men and women in most Western populations, with some evidence of male preponderance in early middle age (Gale and Gillespie, 2001). The incidence of this form of diabetes may, however, differ between both sexes in Japan, because the proportions of persons who were strongly suspected as diabetics were 12.8% for men and 6.5% for women in 2002 (Ministry of Health, Labour and Welfare, 2004). In this study, the ADH2 and ALDH2 genotypes, fasting plasma glucose (FPG) level, weekly alcohol intake, and other possible confounders were examined in Japanese male and female workers separately, to ascertain the impact of these enzyme genotypes on diabetic risk.
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Population and Methods |
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Subjects
A self-reported questionnaire with detailed explanations of the study purpose was distributed to salespersons at motor vehicle dealerships in the central area of Akita Prefecture, northeast Japan, in 2005. From the subjects who returned the questionnaire answered with written informed consent to us (participation rate, approximately 35%), peripheral blood samples for extraction of genomic DNA were obtained at the time of mandatory health checkup, conducted under the Industrial Safety and Health Law in Japan. Of the 799 respondents (600 men and 199 women), eight were excluded because two men and two women were under 20 years of age, one woman was pregnant, and three men did not answer the question on smoking or drinking habit. In addition, 103 men and 13 women were excluded because there were no data on their FPG levels. In total, 492 men and 183 women were enrolled in this study. This study protocol was approved by the ethical review committees of the Akita Health Insurance Union of Motor Vehicle Stores and the Akita University School of Medicine.
Data collection
The weekly amount of each type of alcoholic beverage consumed was asked as previously described (Dakeishi et al., 2004, 2006); e.g., "How many 180-ml cups (or 1800-ml bottles) of sake (Japanese rice wine) do you usually drink in a week?" and "How many 350-ml cans (or, 500-ml cans or 633-ml bottles) of beer do you usually drink in a week?" Types of alcoholic beverages listed were sake, beer, shochu (Japanese distilled alcoholic beverage primarily made from rice, wheat, or sweet potato), whisky, wine, and others (e.g., plum wine, brandy, gin, and vodka). A total of 100% ethanol–equivalent dose (g/week) was calculated for each subject on the assumption that sake, beer, shochu, whisky, and wine contain 15%, 5%, 20% (or 25%), 40%, and 12% ethanol, respectively. Data on FPG, together with age, BMI, and smoking status, were obtained from each record of the health checkup.
ADH2 and ALDH2 genotyping
Genomic DNA was extracted from the peripheral blood of subjects, by using QIAamp DNA blood Mini Kit (QIAGEN Inc., Valencia, CA). Genotypes of ADH2 and ALDH2 were determined by polymerase chain reaction with confronting two-pair primers according to the method of Tamakoshi et al. (2003) with some modification. These procedures were performed by one trained examiner (MD).
Statistical methods
Statistical analyses were conducted in men and women separately. The comparison between the subjects with two different genotypes was made by using Student's t-test or the Fisher's exact test. The significance of the difference in the FPG level after the adjustment for age, BMI, smoking status, and another genotype was analyzed by two-way analysis of variance with the SS model of type II to manipulate ADH2 and ALDH2 genotypes and ethanol intake. As cutoffs for ethanol intake, 70 and 35 g/week were used for men and women, respectively, according to a previous report (Beulens et al., 2007). Smoking status was scored as "nonsmoker" = 0 and "smoker" = 1; also, ADH2 (or ALDH2) was scored as "ADH2*1/1 (ALDH2*1/1)" = 0 and "other genotypes" = 1. All analyses, with two-sided P values, were performed with the Statistical Package for the Biosciences (Murata and Yano, 2002).
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Results |
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Age, BMI, weekly alcohol consumption, and FPG were significantly higher in 492 men than in 183 women (P < 0.001) as shown in Table 1; also, the proportions of drinkers and smokers were higher in men than in women (P < 0.001). The frequencies of the ADH2*1/1, 1/2, and 2/2 genotypes for the men were 6.5%, 38.0%, and 55.5%, respectively; and those for the women were 7.1%, 37.7%, and 55.2%, respectively. Similarly, the frequencies of the ALDH2*1/1, 1/2, and 2/2 genotypes for the men were 77.0%, 21.3%, and 1.6%, respectively; and those for the women were 76.5%, 20.8%, and 2.7%, respectively. These ADH2 and ALDH2 genotypes were in Hardy-Weinberg equilibrium (
2 = 0.14, P = 0.71 for ADH2; 2 = 1.34, P = 0.25 for ALDH2). The FPG levels divided according to ethanol intake (Figure 1) did not differ significantly either among the men (P = 0.824 by one-way analysis of variance) or the women (P = 0.360).
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The values of subgroups divided according to ADH2 and ALDH2 genotypes are listed in Table 2. Regarding the ADH2 genotype, the men with ADH2*1/1 showed significantly higher BMI and FPG levels than the men with ADH2*1/2 or 2/2, and the women with ADH2*1/1 consumed significantly more alcohol than the women with the other genotypes. Regarding the ALDH2 genotype, both the men and women with ALDH2*1/1 consumed significantly more alcohol than those with ALDH2*1/2 or 2/2. However, the FPG levels were significantly higher in the men with ALDH2*1/1 but significantly lower in the women with ALDH2*1/1, as compared to those with the other genotypes.
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When age, BMI, weekly ethanol intake, smoking status, and ADH2 and ALDH2 genotypes were used as independent variables in multiple regression analysis, significant factors affecting the FPG level were age (regression coefficient β = 0.468, P < 0.001), BMI (β = 1.30, P < 0.001), smoking status (β = –3.15, P = 0.025), and ADH2 genotype (β = –9.97, P < 0.001) for the 492 men; and, BMI (β = 1.06, P < 0.001), and ALDH2 genotype (β = 3.03, P = 0.039) for the 183 women. In using analysis of covariance to adjust for age, BMI, alcohol intake, smoking status, and another genotype, the differences in the FPG level between the two subgroups divided according to the ADH2 or ALDH2 genotypes were unsurprisingly significant (P < 0.001 for men and P = 0.039 for women; data not shown). As shown in Table 3, the FPG levels after the adjustment for age, BMI, smoking status, and another genotype were significantly high in the men with ADH2*1/1 and in the women with ALDH2*1/2 or 2/2, as compared to the remaining genotype groups; also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the 183 women (Table 3).
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Discussion |
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The main finding of this study is that the FPG levels differed significantly according to the ADH2 or ALDH2 genotypes in the Japanese men and women. This result was similar when adjusting for the amount of alcohol consumed, BMI, and other possible confounders. The proportion of ADH2*1/1 for our subjects, i.e., 6.9%, is in accordance with other Japanese data (Higuchi et al., 1996
; Yokoyama et al., 2002; Tamakoshi et al., 2003; Suzuki et al., 2006), whereas about 90% of Caucasians have been estimated to possess the ADH2*1/1 genotype (Goedde et al., 1992). Also, the proportion of ALDH2*1/1 for our subjects, 76.4%, was considerably higher than those of 45–59% for other Japanese populations not residing in Akita (Higuchi et al., 1996; Nakamura et al., 2002; Takagi et al., 2002; Yokoyama et al., 2002; Tamakoshi et al., 2003); and, this may help explain the high annual alcohol intake per household in Akita (Ministry of Internal Affairs and Communications, 2002; Dakeishi et al., 2006). In comparison, the proportion of Caucasians with ALDH2*1/1 is approximately 99% (Goedde et al., 1992). Although our result has not yet been confirmed either by other Japanese or Western researchers, it suggests that genotypes of ADH2 and ALDH2 can be crucial confounders in evaluating the association between alcohol intake and diabetes in Mongoloids.
The men with ADH2*1/1 in the current study had significantly higher FPG levels than those with ADH2*2/2 or 1/2. Suzuki et al. (2006) reported that the fasting insulin level was significantly higher in 640 men with ADH2*2/2 than in 346 men with ADH2*1/2, but there was no significant difference in the FPG or hemoglobin A1c (HbA1c) level between the two groups;however, Suzuki et al. did not do the ALDH2 genotyping. In Japanese men, thus, the ADH2 genotype will intervene in the FPG or insulin levels. However, such significant differences in the FPG, insulin, or HbA1c levels were not found between two different ADH2 genotypes among the women of either our study or the above-mentioned study by Suzuki et al. (2006). Further research is required to clarify whether the effect of ADH2 genotype on the FPG or insulin level is predominant in men.
In the present study, the women with ALDH2*1/1 had significantly lower FPG levels than those with the other genotypes, while there was no significant difference in the FPG level between the women consuming alcoholic beverage of <35 g/week and of 35 g/week or more (Table 3). By contrast, the FPG level tended to be higher in the ALDH2*1 homozygous men than in the remaining men (Tables 2 and 3). Although Murata et al. (2000) reported that the plasma HbA1c level of light drinkers (1–400 g/week), before the development of diabetes, was significantly higher in the inactive ALDH2 group than in the active ALDH2 group, their subjects and our female subjects would have no comparability because their subjects were male diabetics and about 20 years older than our subjects. Since Yamaguchi et al. (2007) mentioned that the association of some gene polymorphisms with type 2 diabetes mellitus was sex-specific in Japanese individuals, our findings may imply sex difference in the FPG level due to the ALDH2 genotype. Still, as there were only 10 women with ALDH2*1/2 or 2/2 genotype in one cell of Table 3, a study using a large number of such women should be done to confirm whether the significant difference observed in the FPG level between women with and without ALDH2*1/1 genotype was by chance or not.
We failed to find any significant relation of alcohol intake with the FPG level (Figure 1). The alcohol intake estimated from the same questionnaire as this study correlated significantly with HDL-cholesterol in 1113 salesmen (Dakeishi et al., 2004), which provides qualitative evidence that alcohol intake is being measured with some degree of validity (Giovannucci et al., 1991). Several studies have been performed to confirm the impact of alcohol intake on the incidence of type 2 diabetes (Wannamethee et al., 2002, 2003; Nakanishi et al., 2003; Beulens et al., 2005; Lapidus et al., 2005; Waki et al., 2005), but these results are not always conclusive. For instance, in Japanese lean men, the incidence of diabetes increased with the amount of alcohol consumed (Waki et al., 2005), and there was a U-shaped association between alcohol intake and the incidence of impaired fasting glucose in middle-aged Japanese men (Nakanishi et al., 2003), as well as in the Western population (Carlsson et al., 2005). Four possible reasons for such a disagreement are as follows. First, study populations with different gene predisposition or with a wide range of BMI may have been used. Next, an important factor connected with individual drinking behavior (e.g., salt or sugar intake, total energy intake, or drink timing) may have been disregarded in most studies. Third, since a significant interaction between ethanol intake and ALDH2 genotypes was observed in the women (Table 3), ALDH2 genotype, as well as ADH1C genotype (Beulens et al., 2007), may modify the association between the FPG level and alcohol intake. Finally, the study design and outcomes (e.g., FPG level or diabetic diagnosis) differed among researchers. In any case, since a U-shaped relationship is also seen between the health adverse effect and BMI (Dolan et al., 2007), further research is needed to scrutinize potential factors other than alcohol intake relevant to diabetes.
All observational studies have weaknesses because all important determinants cannot be controlled a priori. In this study, several confounders such as age, BMI, amounts of alcohol consumed, and smoking habit, were considered in the process of data analysis, although physical activity, involved in the incidence of type 2 diabetes (Helmrich et al., 1991; Manson et al., 1991), could not be examined at the time of mandatory health checkup. However, this would not be directly associated with the ADH2 or ALDH2 genotype. Also, we evaluated the effect of one enzyme on glucose metabolism under consideration of another enzyme. In addition, one trained examiner conducted ADH2 and ALDH2 genotyping. Thus, it is suggested that our findings were not heavily influenced by any confounding or measurement bias.
In conclusion, genotypes of ADH2 and ALDH2 can modify the diabetic risk at least in the Japanese population, irrespective of amounts of alcohol consumed. Also, although there is no sex difference in the frequency of the genotypes within the same race, the impacts of these genotypes on glucose metabolism appear to be sex-specific, which may explain the high prevalence of diabetes in Japanese men in comparison to Japanese women. Furthermore, the associations observed between alcohol intake and diabetes in Mongoloids (Nakanishi et al., 2003; Waki et al., 2005) may be renewed by controlling for these genotypes. Nevertheless, further studies with only nondrinkers are necessary to clarify the effect of ADH2 and ALDH2 genotypes on glucose metabolism involved in the development of type 2 diabetes because, of course, even a nondrinker can suffer from the disease.
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ACKNOWLEDGEMENTS |
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This study was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science. We thank Prof. Tatsuya Takeshita, Department of Public Health, Wakayama Medical University, for his valuable advice on ADH2 and ALDH2 genotyping, and Mr. Akio Tamura and Ms. Yumiko Kato for their assistance in data collection.
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