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The Japanese have a polymorphism in the alcohol dehydrogenase 2 gene (ADH2). The alleles of ADH2 (ADH2*1 and ADH2*2) encode more active and less active forms for ethanol metabolism, respectively. We examined whether liver damage and the insulin-glucose axis vary according to ADH2 genotype in the Japanese. The 2,232 subjects (1,126 men and 1,106 women) were recruited from a population-based prospective cohort study. Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, gamma-GTP, and prevalence of diabetes were compared among the ADH2 genotypes. The percentage of drinkers, alcohol consumption, AST, ALT, and gamma-GTP were higher in group ADH2*1/1 than in group ADH2*1/2 or ADH2*2/2 (all P < 0.05). Hence, ADH2*1/1 is associated with excess alcohol intake and liver disorders. However, the prevalence of diabetes did not differ among the three groups. For the glucose-insulin axis, we examined subjects who did not receive insulin therapy or oral anti-diabetes medication. While amounts of alcohol consumed and glucose levels were nearly the same between ADH*1/2 and ADH2*2/2, insulin concentrations were lower in ADH2*2/1 than in ADH2*2/2 (P < 0.05 in men). This finding suggests that the ADH2*1 allele is associated with a lower insulin concentration when alcohol intake is light or moderate. It also suggests that the genetic effect of ADH2*1 plays an important role in alcohol drinking behavior and in the occurrence of liver injury, but the effect is so mild that it does not influence the glucose-insulin axis or prevalence of diabetes.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We and others have previously reported that such a deficiency influences the risk for late-onset Alzheimer's disease (LOAD), hypertension, and myocardial infarction. Then we tried to find phenotypes to which the ALDH2 polymorphism contributes by conducting several evaluations including biochemical and functional analyses of various tissues in a community-dwelling population. Several serum proteins, lipids, and lipid peroxides (LPO) levels showed differences between the nondefective (ALDH2*1/1) and defective (ALDH2*1/2 and ALDH2*2/2) ALDH2 individuals. However, alcohol-drinking behavior is known to affect these evaluations. Thus, we excluded the effects of alcohol-drinking behavior from the association with the ALDH2-deficient genotype through correction and found that the concentration of LPO was significantly lower in the nondefective ALDH2 females than the defective females. The effect of frequent alcohol-drinking behavior in males seems to override the phenotype of the high serum LPO level. These results indicate that the ALDH2 deficiency may enhance oxidative stress in vivo. Thus, these findings suggest that ALDH2 functions as a protector against oxidative stress and the decrease in protection may influence the onset of AD, hypertension, and myocardial infarction.

A -521C-->T polymorphism in the promoter of the dopamine receptor D4 gene (DRD4) has been associated with novelty-seeking behavior in Japanese. Given that the dopaminergic system might also play an important role in bone metabolism, the relation of the -521C-->T polymorphism of DRD4 to bone mineral density (BMD) was examined in 2,228 Japanese subjects (1,123 men; 1,105 women) who were randomly recruited to a population-based, prospective cohort study. BMD at the radius was measured by peripheral quantitative computed tomography, and that for the total body, lumbar spine, right femoral neck, right trochanter, and right Ward's triangle was measured by dual-energy X-ray absorptiometry. Genotype was determined with a fluorescence-based allele-specific DNA primer assay system. For men, BMD for the distal radius, total body, lumbar spine, trochanter, or Ward's triangle was lower in individuals with the CC genotype than in the combined group of TT and TC genotypes or in those with the TT genotype or with the TC genotype. The urinary concentration of deoxypyridinoline was slightly, but significantly, greater in men with the CC genotype than in those with the TT or TC genotypes or with the TT genotype. For women, there were no differences in BMD among -521C-->T genotypes. These results implicate DRD4 as a candidate locus for reduced BMD in Japanese men.

Oxidative stress may affect cellular functions in various pathological conditions, including osteoporosis. Paraoxonase 1 confers antioxidant properties on high-density lipoprotein, with which it is associated, by reducing the accumulation of lipid peroxidation products. We have now examined whether the 584A-->G (Gln192Arg) and 172T-->A (Leu55Met) polymorphisms of the paraoxonase 1 gene and the 959G-->C (Cys311Ser) polymorphism of the paraoxonase 2 gene are associated with bone mineral density (BMD) in community-dwelling Japanese (1,087-1,094 women and 1,112-1,125 men). The subjects were aged 40-79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases. BMD for the lumbar spine and right femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. The 584A-->G and 172T-->A polymorphisms of the paraoxonase 1 gene and the 959G-->C polymorphism of the paraoxonase 2 gene were associated with BMD for the lumbar spine or femoral neck in postmenopausal women, with the 584 GG, 172 TT, and 959 CC genotypes representing risk factors for reduced bone mass. None of these three polymorphisms was associated with BMD in premenopausal women or in men. Our results suggest that the paraoxonase 1 and 2 genes are candidate loci for reduced bone mass in postmenopausal Japanese women.

Transforming growth factor-beta1 (TGF-beta1) is an important regulator of blood pressure (BP) and vascular remodeling, and thus may contribute to the pathogenesis of hypertension. A T-->C transition at nucleotide 869 of the TGF-beta1 gene results in a Leu-->Pro substitution at amino acid 10 of the signal peptide. We have now examined the possible association of the 869T-->C polymorphism of the TGF-beta1 gene with BP and the prevalence of hypertension in 2241 community-dwelling Japanese individuals (1126 men and 1115 women). TGF-beta1 genotype was determined by an allele-specific polymerase chain reaction method. For women, both systolic and diastolic BP was significantly higher in individuals with the CC genotype than in those with the TT or TC genotype. No significant association between TGF-beta1 genotype and BP was detected in men. The frequency of the CC genotype was significantly higher in women with hypertension than in those with normal BP. These results suggest that the TGF-beta1 gene at chromosome 19q13.1 may be a candidate susceptibility locus for hypertension in Japanese women.