Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption.
ABSTRACT There are large individual variations in the responses of risk factors for coronary heart disease to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers.
We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms.
When the workers were divided into three groups: the ADH2(1)/2(1), ADH2(1)/2(2), and ADH2(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In contrast, no difference was observed between the ALDH2(1)/2(1) and (ALDH2(1)/2(2) + ALDH2(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third.
Individuals with the ADH2(1)/2(1) genotype might suffer fewer negative effects of drinking.
Article: Interaction between high-fat diet and alcohol dehydrogenase on ethanol-elicited cardiac depression in murine myocytes.[show abstract] [hide abstract]
ABSTRACT: Consumption of high-fat diet and alcohol is associated with obesity, leading to enhanced morbidity and mortality. This study was designed to examine the interaction between high-fat diet and the alcohol metabolizing enzyme alcohol dehydrogenase (ADH) on ethanol-induced cardiac depression. Mechanical and intracellular Ca2+ properties were measured in cardiomyocytes from ADH transgenic and Friend Virus-B type (FVB) mice fed a low- or high-fat diet for 16 weeks. Expression of protein kinase B (Akt) and Foxo3a, two proteins essential for cardiac survival, was evaluated by Western blot. Cardiac damage was determined by carbonyl formation. High fat but not ADH induced obesity without hyperglycemia or hypertension, prolonged time-to-90% relengthening (TR90), and depressed peak shortening (PS) and maximal velocity of shortening/relengthening (+/- dL/dt) without affecting intracellular Ca2+ properties. Ethanol suppressed PS and intracellular Ca2+ rise in low-fat-fed FVB mouse cardiomyocytes. ADH but not high-fat diet shifted the threshold of ethanol-induced inhibition of PS and +/- dL/dt to lower levels. The amplitude of ethanol-induced cardiac depression was greater in the high-fat but not the ADH group without additive effects. Ethanol down- and up-regulated Akt and Foxo3a expression, respectively, and depressed intracellular Ca2+ rise, the effects of which were exaggerated by ADH, high-fat, or both. High-fat diet, but not ADH, enhanced Foxo3a expression and carbonyl content in non-ethanol-treated mice. Ethanol challenge significantly enhanced protein carbonyl formation, with the response being augmented by ADH, high-fat, or both. Our data suggest that high-fat diet and ADH transgene may exaggerate ethanol-induced cardiac depression and protein damage in response to ethanol.Obesity 01/2008; 15(12):2932-41. · 4.28 Impact Factor
Article: Association analysis of alcohol metabolizing enzymes ADH1B, ADH7, CYP2E1 gene polymorphism with risk for coronary atherosclerosis[show abstract] [hide abstract]
ABSTRACT: The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5′-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B * G (+MslI) allele, CYP2E1 * C2 (+PstI) allele and CYP2E1 * C (-DraI) allele were 8.48 ± 1.86, 1.20 ± 0.69, and 10.00 ± 1.90%, respectively. The ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7 * C (-StyI) allele was 44.58 ± 3.21%. A significantly higher frequency of CYP2E1 PstI C2 allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03–20.01). The tendency to significant effect of A1A2 genotype in ADH1B MslI polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0.042) were also revealed. Association of A1A2 genotype in ADH1B MslI polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.Russian Journal of Genetics 02/2007; 43(3):323-329. · 0.43 Impact Factor
Article: The association of alcohol and alcohol metabolizing gene variants with diabetes and coronary heart disease risk factors in a white population.[show abstract] [hide abstract]
ABSTRACT: Epidemiological studies have shown a J- or U-shaped relation between alcohol and type 2 diabetes and coronary heart disease (CHD). The underlying mechanisms are not clear. The aim was to examine the association between alcohol intake and diabetes and intermediate CHD risk factors in relation to selected ADH and ALDH gene variants. Cross-sectional study including 6,405 Northern European men and women aged 30-60 years from the general population of Copenhagen, Denmark. Data were collected with self-administered questionnaires, a physical examination, a 2 hour oral glucose tolerance test, and various blood tests. J shaped associations were observed between alcohol and diabetes, metabolic syndrome (MS), systolic and diastolic blood pressure, triglyceride, total cholesterol, and total homocysteine. Positive associations were observed with insulin sensitivity and HDL cholesterol, and a negative association with insulin release. Only a few of the selected ADH and ALDH gene variants was observed to have an effect. The ADH1c (rs1693482) fast metabolizing CC genotype was associated with an increased risk of impaired glucose tolerance (IGT)/diabetes compared to the CT and TT genotypes. Significant interactions were observed between alcohol and ADH1b (rs1229984) with respect to LDL and between alcohol and ALDH2 (rs886205) with respect to IGT/diabetes. The selected ADH and ALDH gene variants had only minor effects, and did not seem to markedly modify the health effects of alcohol drinking. The observed statistical significant associations would not be significant, if corrected for multiple testing.PLoS ONE 01/2010; 5(8):e11735. · 4.09 Impact Factor