Erythrocyte mean cell volume and genetic polymorphism of aldehyde dehydrogenase 2 in alcohol drinkers

The amount of alcohol consumed correlates with the values of different laboratory parameters. Although one of the most frequently used markers of alcohol consumption is the erythrocyte mean cell volume (MCV), the extent of the increase of MCV varies from one individual to another.1 This cannot be explained only by inaccuracies in measuring alcohol intake by interviews or questionnaires. The major enzymes responsible for alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Among the ADH and ALDH genes, the polymorphisms of ADH2 and ALDH2 are thought to contribute to individual differences in the elimination rates of alcohol and acetaldehyde, respectively.2 In this study, we examined the relations between the polymorphisms of these genes and the levels of MCV in drinkers.

The subjects were 133 male workers aged 25 to 59 years (average, 46 years) who drank more than 300 g alcohol per week (average, 375 g). Informed consent was obtained from all subjects. DNA was extracted from peripheral blood leukocytes. The ADH2genotype was determined by polymerase chain reaction and subsequent digestion with MaeIII according to the method of Xu et al.3 The ALDH2 genotype was determined based on amplified product length polymorphism analysis using 3 oligonucleotide primers according to the method described by Aoshima et al.4 For statistical analysis, the Tukey multiple comparison test was used to assess significant differences between group means. Analysis of covariance was used to estimate the means of variables adjusted for the confounding variables.

In the 133 men, the frequencies ofALDH2¹/2¹, ALDH2¹/2², andALDH2²/2² genotypes were 78.9%, 20.3%, and 0.8%, respectively. The frequency of theALDH2¹/2¹ genotype was higher, and the frequencies of the ALDH2¹/2² andALDH2²/2² genotypes were lower, compared with those in Japanese subjects, including drinkers and nondrinkers.5 This is probably because we examined only heavy drinkers. When the subjects were divided into theALDH2¹/2¹, ALDH2¹/2², andALDH2²/2² groups, theALDH2¹/2² group had significantly higher MCVs than the ALDH2¹/2¹ group (Table 1). No difference in hemoglobin level between the 2 groups was observed. Similar results were obtained after correction for age, body-mass index, smoking, alcohol consumption, and ADH genotype. Because theALDH2²/2² genotype was observed in only one subject, we could not compare this group with the other 2 groups. In contrast, when the subjects were divided into theADH2¹/2¹, ADH2¹/2², andADH2²/2² groups, no difference in the MCVs and hemoglobin concentration was observed among the 3 groups. Multiple regression analysis revealed that MCV was positively associated with the ALDH genotype (P = .0001), the amount of smoking (P = .0208), and age (P = .0237), but negatively associated with the body-mass index (P = .0374). There was no association between MCV and the amount of consumption or the ADH genotype.

The present study indicated that the extent of the increase of MCV in alcohol drinkers depended on the individual ALDHgenotype. Although drinkers are well known to show macrocytosis, the cause of their macrocytosis is not clear. Because the ALDH2genotype is largely responsible for blood levels of acetaldehyde after alcohol consumption, the macrocytosis observed in drinkers might be caused by increased blood levels of acetaldehyde.

Supported in part by grants from the Health Science Center Foundation, the Smoking Research Foundation, and the Clinical Pathology Research Foundation of Japan