ALDH2*2 and peer drinking in East Asian college students

Background: The ALDH2*2 allele (A-allele) at rs671 is more commonly carried by Asians and is associated with alcohol-related flushing, a strong adverse reaction to alcohol that is protective against drinking. Social factors, such as having friends who binge drink, also contribute to drinking in Asian youth. Objectives: This study examined the interplay between ALDH2*2, peer drinking, and alcohol consumption in college students. We hypothesized that the relationship between ALDH2*2 and standard grams of ethanol per month would vary based on the level of peer drinking. Methods: Subjects (N = 318, 63.25% female) were East Asian college students in the United States who reported drinking alcohol. Data were from the freshman year of a university survey that included a saliva DNA sample. ALDH2*2 status was coded ALDH2*2(+) (A/G and A/A genotypes) and ALDH2*2(?) (G/G genotype). Peer drinking was students’ perception of how many of their friends “got drunk”. Results: Main effects of ALDH2*2(?) and having more friends who got drunk were associated with greater alcohol consumption. The ALDH2*2 × peer drunkenness interaction showed a stronger positive association with alcohol consumption for ALDH2*2(?) versus ALDH2*2(+) at increasing levels of peer drunkenness. Follow-up comparisons within each peer drunkenness level identified significantly higher alcohol consumption for ALDH2*2(?) compared to ALDH2*2(+) at the all friends got drunk level.

Conclusion: There was evidence of a stronger effect for ALDH2*2(?) compared to ALDH2*2(+) with greater alcohol use when students were more exposed to peer drinking. Findings contribute to a growing literature on the interrelationships between genetic influences and more permissive environments for alcohol consumption.     

Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele

BACKGROUND: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. METHODS: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. RESULTS: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. CONCLUSIONS: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.     

ALDH2/ADH2 Polymorphism Associated with Vasculopathy and Neuropathy in Type 2 Diabetes

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N¹-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.     

CYP2E1 and ALDH2 Genotypes and Alcohol Dependence in Japanese

The genotypes of the CYP2E1 and ALDH2 loci of alcoholic (alcohol dependence) and nonalcoholic (healthy) Japanese were investigated to examine the relationship between the polymorphism of CYP2E1 (C₁/C₂) and ALDH2 ( ALDH2*1/ALDH2*2 ), and the susceptibility to alcoholism. There was no significant difference in C₂ gene frequency between alcoholics (0.19) and nonalcoholics (controls) (0.20), whereas there was a significant difference in ALDH2 allele frequency, suggesting that, in Japanese, the C₂ genotype of CYP2E1 may have nothing to do with the risk of developing alcohol dependence. However, the ALDH2*1 allele may influence drinking behavior and the development of alcohol dependence. Furthermore, racial interethnic differences in the frequency of the mutated allele of the CYP2E1 gene (CJ were found, like the ALDH2 gene. Japanese healthy controls showed a significantly higher frequency of the C₂ allele than did Swedish healthy controls (0.05; reported by Persson et al., FEBS Lett. 319:207-211,1993).     

ALDH2基因rs671位点与中国人群心血管代谢危险因素的关系

目的探讨乙醛脱氢酶2(ALDH2)基因rs671位点与我国人群心血管代谢危险因素的关系。方法利用2000~2001年开展的中国心血管健康多中心合作研究(InterASIA),纳入北方5个省市共计6404例基线未患冠心病和脑卒中个体。分析rs671位点与11种心血管代谢危险因素(腰臀围、血脂和血压等)的关系。结果rs671 A等位基因频率为0.16。rs671与饮酒行为显著相关,携带A等位基因的个体不倾向于饮酒(P<0.001)。rs671与腰围、臀围、甘油三酯和舒张压显著相关(P<0.05),每增加一个A等位基因,分别减少0.61 cm、0.54 cm、4.39 mg/dl和0.68 mmHg。进一步校正饮酒行为后,rs671与臀围的关联仍然显著(P=0.035),但与舒张压的关联不再显著。在饮酒人群中rs671 A等位基因可降低舒张压1.28 mmHg,而在非饮酒人群中没有作用。结论本研究发现rs671位点与中国人群腰围和舒张压显著相关,其中与舒张压的关联主要是通过饮酒发挥作用的。     

Effect of ALDH2 and CYP2E1 Gene Polymorphisms on Drinking Behavior and Alcoholic Liver Disease in Japanese Male Workers

Aims: We examined the relationships of ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease in Japanese male workers.
Methods: Two hundred and eighty-seven Japanese men were selected from one metal company to adjust for similar economic and social backgrounds. Drinking behavior was assessed from a self-assessment questionnaire. Genotypes of ALDH2 and CYP2E1 were analyzed with the polymerase chain reaction-single strand conformation polymorphism and with the polymerase chain reaction-restriction fragment length polymorphism, respectively.
Results: The frequency of the ALDH2 genotype was 55% for typical homozygotes, 42% for heterozygotes, and 4% for atypical homozygotes. The frequency of the CYP2E1 genotype was 62% for c1 homozygotes, 35% for heterozygotes, and 3% for c2 homozygotes. The ALDH2 genotype closely influenced drinking habits, but not the CYP2E1 genotype. Among habitual drinkers, ALDH2 typical homozygotes consumed significantly larger amounts of ethanol than ALDH2 heterozygotes, whereas CYP2E1 genotypes did not influence daily alcohol consumption. Sixteen men (5.6%) were diagnosed with alcoholic liver disease. In terms of ALDH2 genotypes, 12 cases (7.6%) were typical homozygotes and 4 (3.4%) were heterozygotes, whereas the incidence of alcoholic liver disease was not different between c1/c1 homozygotes and c1/c2 heterozygotes. When the interactive contribution of the ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease were examined, there were no significant differences in the CYP2E1 genotype among the subjects with the same ALDH2 genotype.
Conclusion: The ALDH2 genotype is strongly associated with individual alcohol drinking behavior and the development of alcoholic liver disease in Japanese male workers, but the CYP2E1 genotype is not.     

Inactive Aldehyde Dehydrogenase 2 Worsens Glycemic Control in Patients With Type 2 Diabetes Mellitus Who Drink Low to Moderate Amounts of Alcohol

Background: Alcohol intake can have hypoglycemic or hyperglycemic effects in patients with type 2 diabetes mellitus. The present study was designed to investigate the glycemic control of male patients with diabetes mellitus from the aspect of the genetic status of alcohol metabolism. Methods: One hundred sixty-three men with type 2 diabetes mellitus were enrolled in the present study. They were all outpatients at the Diabetes Center of Saiseikai Central Hospital. The genotype of the aldehyde dehydrogenase 2 (ALDH2) gene of each patient was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the patients were divided into those with active or inactive ALDH2 phenotype. We compared the amount of habitual alcohol intake and clinical data that included physical findings and blood chemistry of the patients in the active and inactive ALDH2 groups. The glycemic control of each patient was evaluated by the serum level of HbA1c. Results: Of the 163 patients with type 2 diabetes mellitus, 90 patients had the active ALDH2 phenotype and 73 patients had the inactive ALDH2 phenotype. The mean HbA1c level of the active ALDH2 group was nearly the same as that of the inactive ALDH2 group. However, the HbA1c level of the light-to-moderate drinkers (1-400 g/week) in the inactive ALDH2 group was highest and was significantly higher than the HbA1c level of the light-to-moderate drinkers of the active ALDH2 group. The HbA1c of the patients with diabetic complications was higher than the HbA1c of those without diabetic complications in both the active and inactive ALDH2 groups. However, the HbA1c level of the light-to-moderate drinkers without diabetic complications in the inactive ALDH2 group was significantly higher and the incidence of 24 hr urinary C-peptide was higher than the respective level of the light-to-moderate drinkers without diabetic complications in the active ALDH2 group. Conclusions: Habitual light-to-moderate alcohol intake worsens glycemic control in diabetic patients who have the inactive ALDH2 phenotype. The data on 24 hr urinary C-peptide level suggested that increased acetaldehyde after light-to-moderate drinking by inactive ALDH2 diabetic patients may increase the HbA1c value by the insulin-resistant condition that resulted in hyperinsulinemia.     

Alcohol Dehydrogenase-2*2 Allele is Associated With Decreased Prevalence of Fetal Alcohol Syndrome in the Mixed-Ancestry Population of the Western Cape Province, South Africa

BACKGROUND: Fetal alcohol syndrome (FAS) is particularly common among the mixed-ancestry population of the Western Cape Province of South Africa and occurs at a frequency of 0.0392-0.0429 (39.2-42.9 of 1000) among 5- to 9-year-old school entrants. While FAS is clearly caused by an environmental insult, studies in twins and mice support a significant genetic contribution to risk for FAS. It is likely that the development of FAS following excessive alcohol exposure is influenced by genetic factors in both the mother and the child. Known polymorphisms of the alcohol dehydrogenase-2 (ADH2) gene resulting in isozymes with different alcohol oxidizing capacities were investigated as possible candidates for influencing the risk for FAS. METHODS: Genotyping was undertaken for the ADH2 locus in 56 FAS-affected children, their 56 mothers, and 178 control individuals of mixed ancestry from the same geographic region. The ADH2 alleles were analyzed for the three groups and the allele frequencies of the mother and FAS-affected children were independently compared with the control group. RESULTS: The ADH2*2 allele was found to be significantly more common in the control group than in the mothers of FAS-affected children (p = 0.025 +/- 0.004) and in the FAS subjects (p = 0.025 +/- 0.004). The ADH2*3 allele frequency was low and was not significantly different between the groups. CONCLUSION: The ADH2*2 allele is significantly more common in control individuals, suggesting that it may either confer protection or be a marker for a protective effect against FAS among individuals of mixed ancestry in the Western Cape Province of South Africa.     

Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages

BACKGROUND: Previously, we created an aldehyde dehydrogenase 2 gene transgenic (Aldh2-/-) mouse as an aldehyde dehydrogenase (ALDH) 2 inactive human model and demonstrated low alcohol preference. In addition, after a free-choice drinking test, no difference in the acetaldehyde level was observed between the Aldh2-/- and wild type (Aldh2+/+) mice. The actual amounts of free-choice drinking were so low that it is uncertain whether these levels are pharmacologically and/or behaviorally relevant in either strain. To elucidate this uncertainty, we compared the ethanol and acetaldehyde concentration in the blood, brain, and liver between the Aldh2-/- and Aldh2+/+ mice after ethanol gavages at the same dose and time. METHOD: We measured differences in the ethanol and acetaldehyde levels between the Aldh2-/- and Aldh2+/+ mice by headspace gas chromatography-mass spectrometry (GC-MS) after ethanol gavages at the same dose and time. RESULTS: Significantly higher blood acetaldehyde concentrations were found in the Aldh2-/- mice than in the Aldh2+/+ mice 1 hr after the administration of ethanol gavages at doses of 0.5, 1.0, 2.0, and 5.0 g/kg. The blood acetaldehyde concentrations in the two strains were 2.4 vs. 0.5, 17.8 vs. 1.9, 108.3 vs. 4.3, and 247.2 vs. 14.0 (microM), respectively. In contrast, no significant difference was observed in the blood ethanol concentrations between the Aldh2+/+ and Aldh2-/- mice. The aldehyde dehydrogenase 2 enzyme metabolized 94% of the acetaldehyde produced from the ethanol as calculated from the area under the curve (AUC) of acetaldehyde when ethanol was administered at a dose of 5.0 g/kg. CONCLUSIONS: These data indicate that mouse ALDH2 is a major enzyme for acetaldehyde metabolism, and the Aldh2-/- mice have significantly high acetaldehyde levels after ethanol gavages.     

Comparison of hyperglycemia,hypertension, and hypercholesterolemia management in patients with type 2 diabetes

PURPOSE: Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. We compared hyperglycemia management with the management of the cardiovascular disease risk factors hypertension and hypercholesterolemia in a cohort of type 2 diabetes patients. SUBJECTS AND METHODS: We randomly selected 601 patients with type 2 diabetes seen at the outpatient practices of an academic medical center and assessed the care they received during an 18-month period. We compared proportions of patients who had hemoglobin A(1c) (HbA(1c)) levels, blood pressure, or total cholesterol levels measured; who had been prescribed any drug therapy if HbA(1c) levels, systolic blood pressure, or low-density lipoprotein (LDL) cholesterol levels exceeded recommended treatment goals; and who had been prescribed greater-than-starting-dose therapy if these values were above those of treatment goals. RESULTS:Patients were less likely to have cholesterol levels (76%, n = 455) measured than HbA(1c) (92%, n = 552) levels or blood pressure (99%, n = 595; P <0.0001 for either comparison). The proportion of patients that received any drug therapy was greater for above-goal HbA(1c) (92%, n = 348) than for above-goal systolic blood pressure (78%, n = 274) or LDL cholesterol (38%, n = 82; P <0.0001 for each comparison). Similarly, patients whose HbA(1c) levels were above the treatment goal (80%, n = 302) were more likely to receive greater-than-starting-dose therapy, compared with those who had above-goal systolic blood pressure (62%, n = 218) and LDL cholesterol levels (13%, n = 28; P <0.0001). CONCLUSION: In this cohort, hypercholesterolemia and hypertension were managed less aggressively than was hyperglycemia. Given the prevalence of cardiovascular disease in patients with type 2 diabetes, increased screening for hypercholesterolemia and more aggressive drug therapy for hypercholesterolemia and hypertension are needed.     

ALDH2 and ADH1B interactions in retrospective reports of low-dose reactions and initial sensitivity to alcohol in Asian American college students

Background: A mechanistic model has been proposed for how alcohol‐metabolizing gene variants protect individuals from the development of alcohol use disorders, with heightened sensitivity to alcohol being an early step (endophenotype) in this model. This study was designed to determine whether possession of 2 alcohol‐metabolizing genes variations, the aldehyde dehydrogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self‐reported sensitivity to alcohol at low doses and at initial use. Methods: Asian–American college students (N = 784) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol symptoms following 1 or 2 drinks and level of response to alcohol during the first 5 lifetime drinking episodes. Results: Participants who had an ALDH2*2 allele were more likely to report experiencing all 6 low‐dose symptoms and having heightened initial response to alcohol. An interaction was found between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self‐reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele. Conclusions: These findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol‐related problems.     

Poor metabolic control and predisposition to hypertension,rather than hypertension itself,are risk factors for nephropathy in type 2 diabetes

Sodium-lithium countertransport (Na⁺/ Li⁺ CT) activity in erythrocytes has been shown to be high in a subset of patients with essential but not secondary hypertension and in type 1 (insulin-dependent) diabetic patients with nephropathy. More recently it has been shown that the presence of a major gene for Na⁺/Li⁺ CT, or another closely linked gene, rather than the actual level of Na⁺/Li⁺ CT, increases the risk of hypertension onset. The aim of the present study was to investigate whether Na⁺/Li⁺ CT activity is associated with hypertension and nephropathy in type 2 (non-insulin-dependent) diabetes. We studied 18 type 2 diabetic patients with normal blood pressure levels (systolic 140 and diastolic 85 mmHg) and albumin excretion rate (15 g/min), 19 type 2 diabetic patients with hypertension (systolic 145 and diastolic 90 mmHg) and a normal albumin excretion rate (15 g/min) and 19 type 2 diabetic patients with an increased albumin excretion rate (20 g/min), irrespective of blood pressure levels. Eighteen normal subjects, matched for sex and age, served as controls. Na⁺/Li⁺ CT activity in erythrocytes was higher in type 2 diabetics with a high albumin excretion rate (486±148 mol/l erythrocytes per hour,P<0.01) and in hypertensive diabetics (410±129,P<0.05), but not in normotensive diabetics (340±141), than in controls (282±96) (mean±SD). Body mass index was higher in diabetics with hypertension and in those with an abnormal albumin excretion rate than in normotensive diabetics and controls. Blood pressure levels were higher in diabetic patients with an increased albumin excretion rate than in normotensive diabetics and controls. Of diabetic patients with a high albumin excretion rate 26% had normal diastolic blood pressure levels. Diabetics with a high albumin excretion rate had higher glycated haemoglobin, cholesterol and triglyceride levels and a longer duration of diabetes than hypertensive diabetics with a normal albumin excretion rate. The association of these clinical features in type 2 diabetes closely resembles that previously reported in type 1 diabetes. A novel finding of the present study is that predisposition to hypertension, as indicated by high Na⁺/Li⁺ CT, seems to confer a susceptibility to the development of renal damage in type 2 diabetes, partially independent of blood pressure levels per se, and that diabetic patients with high Na⁺/Li⁺ CT and hypertension are, to some extent, protected against the development of nephropathy when the metabolic control is tighter and the duration of the disease shorter.