Effect of alcohol and aldehyde dehydrogenase gene polymorphisms on alcohol-associated hypertension: the Guangzhou Biobank Cohort Study

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The Association of Alcohol and Alcohol Metabolizing Gene Variants with Diabetes and Coronary Heart Disease Risk Factors in a White Population

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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

Alcohol and Acetaldehyde in Public Health: From Marvel to Menace

Alcohol abuse is a serious medical and social problem. Although light to moderate alcohol consumption is beneficial to cardiovascular health, heavy drinking often results in organ damage and social problems. In addition, genetic susceptibility to the effect of alcohol on cancer and coronary heart disease differs across the population. A number of mechanisms including direct the toxicity of ethanol, its metabolites [e.g., acetaldehyde and fatty acid ethyl esters (FAEEs)] and oxidative stress may mediate alcoholic complications. Acetaldehyde, the primary metabolic product of ethanol, is an important candidate toxin in developing alcoholic diseases. Meanwhile, free radicals produced during ethanol metabolism and FAEEs are also important triggers for alcoholic damages

Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian Randomization Approach

Using a mendelian randomization approach Sarah Lewis and colleagues find strong support for the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension

Alcohol and the heart: to abstain or not to abstain?

Alcohol has been consumed by most societies over the last 7000 years. Abraham Lincoln said It has long been recognized that the problems with alcohol relate not to the use of a bad thing, but to the abuse of a good thing. Light to moderate alcohol consumption reduces the incidence of coronary heart disease (CHD), ischemic stroke, peripheral arterial disease, CHD mortality, and all-cause mortality, especially in the western populations. However, heavy alcohol consumption is detrimental causing cardiomyopathy, cardiac arrhythmias, hepatic cirrhosis, pancreatitis, and hemorrhagic stroke. In this article, we review the effects of alcohol on CHD, individual cardiovascular risk factors, cardiomyopathy, and cardiac arrhythmias, including the most recent evidence of the effects of alcohol on CHD

GENETIC AND MOLECULAR FACTORS IN THE AETIO-PATHOGENESIS OF PANCREATITIS IN HUMANS

Both acute (AP) and chronic (CP) pancreatitis are complex diseases, with a number of aetiologies and complex pathogeneses. A number of contributing factors are assessed here. Genetic studies were performed looking at a high activity polymorphism of the alcohol metabolising enzyme cytochrome P450 2E l. Assessing a role in alcohol abuse and end organ disease; alcohol abusers (n= 239) and controls (n= 208) were studied. A significantly lower number of alcohol consumers (2.1 %) had the polymorphism than controls (5.8%); p= 0.049, Fisher's exact test. Any association with end organ disease could not be further elucidated due to the rarity of the polymorphism in this population. In another genetic study, looking at a polymorphism in interleukin-1a, no associations were found with CP; of note no associations were found with genotypes implicated in AP. A double-blind, placebo controlled crossover trial of a leukotriene receptor antagonist in chronic pancreatitis revealed no benefit. Studies of production of arachidonic acid metabolites leukotriene E4 (LTE4), prostaglandin E2 (PGE2) and (a known marker of mast cell activation) prostaglandin D2 (11β-PGF2a) were performed. Analysis looked at both acute (n= 19) and chronic pancreatitis (n= 19), employing age and sex matched controls. The LTE4 studies did not reveal any significant difference in levels. PGE2 levels were not different between CP patients and controls while they were significantly higher in AP than controls; p= 0.006, independent samples t-test. The variation appeared most marked for mild disease; one way ANOVA p= 0.024 and direct comparison of patients with mild disease and their matched controls; p= 0.011. The 11β-PGF2a study conversely showed no difference in AP but significantly higher levels in CP in comparison to their matched controls; p= 0.001, Mann Whitney U test. Based on a previous pilot study in CP and a difference in variance of LTE4 in AP in the above study, a genetic study of the known functional polymorphism in the gene of leukotriene C4 synthase (the first dedicated enzyme in the formation of the cysteinyl leukotrienes) was performed. Controls totalled 108 subjects; AP 238 (mild= 169 patients; severe= 69) and CP 57 subjects; no difference in the genotype or allele frequencies were found. In summary: A possible role for a functional polymorphism in cytochrome P450 2E1 (not previously examined in patient groups) in protection against alcoholism has been identified. Perhaps analogous to the protection associated with high activity forms of alcohol dehydrogenase and low activity forms of aldehyde dehydrogenase. PGE2 is elevated in acute pancreatitis in humans consistent with the majority of the data in animals. Again consistent with the bulk of animal data this appears to be most marked in mild disease, possibly indicating a protective, and therefore potentially therapeutic, role. 11β-PGF2a, a metabolite of PGD2 and marker of mast cell activation, is elevated in chronic but not acute pancreatitis. This implicates mast cells in chronic pancreatitis and would be consistent with their known role in fibrosis and tissue remodelling and suggests a possible therapeutic target

A Study of Biochemical, Pharmacokinetic, Physiological and Psychomotor Variables and Ethanol Sensitivity after Low-dose Ethanol

The influence of ALDH2 and ADH2 genotype on the biochemical, physiological, psychomotor and subjective responses of Asian subjects to a challenge dose of ethanol were investigated. One hundred and ten healthy male and female subjects of fill] or partial North East Asian descent (with ancestral origins in China, Japan, Korea and Vietnam), who were living in Australia at the time of testing, were genotyped for alcohol dehydrogenase (ADHz) and aldehyde dehydrogenase (ALDHz) enzymes using a combination of the polymerase chain reaction (PCR) with restriction enzyme digestion, allele specific oligonucleotide probing, or constant denaturant gel electrophoresis methods. Volunteers were given a low oral dose (0.3 g kg^-1) of ethanol and were assessed subjectively for their degree of flush and for performance impairment using a battery of psychomotor tests (including divided attention, digit symbol coding, standing steadiness and critical flicker fusion frequency threshold). Self-report questionnaires were used to assess the subjects' perception of their intoxication and impairment. Blood ethanol concentrations (BECs) were monitored by breath analysis every fifteen minutes and blood samples were obtained from subjects before and at 15, 60 and 120 minutes afier ethanol administration. Measurements were made of the blood or plasma levels of acetaldehyde, acetate, pyruvate, lactate and ethanol. The blood pressure (systolic and diastolic), heart rate and facial temperature were also recorded at regular intervals. The effects of the ADHz genotype, ALDH; genotype, ALDHZ/ ADHz combination genotype, the degree of flush and gender on the psychomotor performance, physiological, biochemical, pharmacokinetic and subjective responses of the subjects were explored to determine their influence on the response to ethanol. When subjects were classified by ALDHz genotype, the BEC curve, acetaldehyde concentration, acetate concentration, facial temperature, heart rate, critical flicker fusion frequency threshold, digit symbol coding reaction time, standing steadiness and divided attention delay and excursion were all affected by whether the subject was ALDH; Homoll, Het or Hom022. The psychomotor performance of ALDHz Hom022 subjects was found to be more impaired in the divided attention delay, excursion and digit symbol coding reaction time tasks than in either Het or Homoll subjects. The standing steadiness epoch time and critical flicker fusion frequency threshold were also most affected by ethanol in the ALDHz Hom022 group. The effect of ethanol on the pyruvate concentration, heart rate, CFFF threshold and standing steadiness also differed significantly among subjects of different ADH; genotype. The ADHz Homozygote-22 (Hom022) subjects had a higher standing steadiness epoch time and critical flicker fusion frequency threshold than either Heterozygote (Het) or Homozygote—ll (Homol 1) subjects. The subjectively rated degree of flush was associated with differences in acetaldehyde concentration, acetate concentration, digit symbol coding reaction time, divided attention delay, facial temperature and heart rate measured. Psychomotor impairment in the divided attention delay task was greatest for the subjects who flushed with intermediate severity, although at two hours post-ethanol, the group which produced the most severe flushing was more severely affected. In the digit symbol coding reaction time, the subjects who produced the most severe flushing reactions were also most impaired