ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes (original) (raw)
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Genetic and Environmental Influences on Alcohol Metabolism in Humans
Alcoholism: Clinical and Experimental Research, 2001
This manuscript represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Ting-Kai Li. The presentations were: (1) Introduction to the Symposium, by Ting-Kai Li; (2) ALDH2 polymorphism and alcohol metabolism, by Shih-Jiun Yin; (3) ALDH2 promoter polymorphism and alcohol metabolism, by David W. Crabb; (4) Use of BrAC clamping to estimate alcohol elimination rates: Application to studies of the influence of genetic and environmental determinants, by Sean O'Connor; and (5) Effect of food and food composition on alcohol elimination rates as determined by clamping, by Vijay A. Ramchandani.
A Preliminary Data: Distribution of ADH1C Genotypes and Alleles in Turkish Alcoholic Subjects
group (23%) compared to that of the alcohol-dependents (42%, p ! 0.0001). We obtained no statistically significant difference among the ADH1C genotype groups regarding age. Conclusions: These findings suggest that a significantly higher presence of ADH1C * 2 allele is associated with alcohol dependence in a Turkish population. Studies with other related polymorphisms are needed to more precisely estimate the association of alcohol dependence with ADH1C .
Genetics of Alcohol Use in Humans: An Overview
… JOURNAL OF HUMAN …, 2008
Alcoholism is an extremely complex disease for which no generally accepted definition exists. There is a complex interaction between the socio-environmental context, the individual at risk, and the availability of alcohol. The result of family, twin and adoption studies suggest a significant genetic predisposition to the disease. Identifying novel genetic risk factors for common diseases is a global challenge in the post genomic era. Recent molecular genetic research into the causes of alcoholism has drawn attention to the potential role of alcohol and acetaldehyde metabolizing enzymes. Functional polymorphisms have been observed at various genes encoding these enzyme proteins that act as one of the biological determinants significantly influencing drinking behavior and the development of alcoholism and alcohol-induced organ damage. Most ethanol elimination occurs by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) systems via oxidation of ethanol to acetaldehyde and acetic acid. However, the legacy of alcoholism among certain ethnic groups suggests that genetic factors can increase an individual's vulnerability for this disease. An association study in patient cohorts and controls, from large populations involving whole genome scans, is the preferred approach for complex traits. To understand the molecular epidemiology and role of cofactors in alcoholism the standard phenotype-genotype correlation may be a useful tool. The present paper reviews various aspects of alcoholism including both the behavioural and molecular etiologies.
ADH single nucleotide polymorphism associations with alcohol metabolism in vivo
Human Molecular Genetics, 2009
We have previously found that variation in alcohol metabolism in Europeans is linked to the chromosome 4q region containing the ADH gene family. We have now typed 103 single nucleotide polymorphisms (SNPs) across this region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge. In vivo alcohol metabolism was modelled with three parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1B and ADH4 regions. Rate of elimination was associated with SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease. The combined SNP associations with early-and late-stage metabolism only account for approximately 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region is yet to be explained.
Addiction, 2010
Background Standardized death rates from chronic liver diseases (CLDs) in Hungary are much higher than the European Union average. Carrying the alcohol dehydrogenase 1B 48His allele (rs1229984 or ADH1B*2) could decrease the risk of alcoholism, but with persistent drinking may confer a greater risk of CLDs. The aim of this study was to assess the prevalence of this polymorphism in the Hungarian population and its association with alcohol consumption and with CLDs.Methods and results A total of 278 cases with diagnosed CLDs and 752 controls without any alterations in liver function, all males aged 45–64, were screened for ADH1B Arg48His polymorphism. ADH1B*2 allele frequencies in controls and cases were 8.31% and 4.50%, respectively (χ2 = 9.2; P = 0.01). Carrying the ADH1B*2 allele was associated with significantly lower odds ratio (OR) for drinking frequency (OR = 0.63; P = 0.003), the number of positive answers on CAGE (Cut-down, Annoyed, Guilt, Eye-opener) assessment (OR = 0.58; P = 0.005) and a positive CAGE status (OR = 0.55; P = 0.007). There was a significant association between ADH1B*2 and CLDs (OR = 0.50; P = 0.003), but it disappeared after adjusting for CAGE status and scores (OR = 0.67 P = 0.134; OR = 0.67 P = 0.148, respectively) and weakened after adjusting for drinking frequency (OR = 0.61; P = 0.045). Among heavy drinkers the presence of ADH1B*2 did not increase the risk of cirrhosis but there was a significant interaction between genotype and CAGE status (P = 0.003, P = 0.042), with ADH1B*2 conferring reduced risk of CLDs in CAGE negatives.Conclusion In Hungarians, the ADH1B 48His allele reduces the risk of alcoholism, but not the risk of chronic liver disease among heavy drinkers.
Alcoholism: Clinical and Experimental Research, 2006
Background: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. Methods: Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. Results: The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. Conclusions: Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.
https://www.ijhsr.org/IJHSR\_Vol.7\_Issue.3\_March2017/IJHSR\_Abstract.048.html, 2017
Background: Health problems related to lifestyle and behavior are increasingly common in modern societies. Chronic alcoholism and its related disorder are one of the major problems in the world. Chronic alcohol abuse will cause the drinker to lose control of his or her drinking. the social problems arising from alcoholism are serious and caused by the pathological changes in the brain as well as psychiatric disorder are common in alcoholic with as many as 25 percent suffering from severe psychiatric disturbances. Prolonged alcohol consumptions affect the liver enzymes such as Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline phosphatase (ALP) and Gamma Gutamyltransferase (GGT). In this study we found that genetic polymorphism of the patatin like phospholipase-3 I148M variant (rs738409 C>G) encoding for an isoleucine to methionine substitution, a gene coding for a transmembrane protein most prominently expressed in the hepatocytes due to excessive alcohol consumption. The effect of alcohol consumption on lipoprotein in cholesterol transport as well as novel effects of lipoproteins on vascular cell wall, comprise a complex mechanism through which alcohol is cardioprotective. Aim: To recognize which factors affect of alcohol consumption on liver enzymes, High density lipoprotein cholesterol and genetic aspects, in this light of current knowledge on this matter. Methods: We performed a structured literature review identifying studies focusing on the effect of alcohol consumption on the liver enzymes, HDL-Cholesterol and other factors. Results: In addition to the prolonged alcohol intake and alcohol consumption patterns, such as gender, genetic background, oxidative stress, metabolism abnormalities play a key role in the effect of liver enzymes, HDL-cholesterol and genetic aspects as well as health related disorder. Conclusions: Understanding the risk factors of excessive alcohol consumption on liver and liver enzymes and high density lipoprotein cholesterol. Moderate alcohol intake is beneficial for heart related problems. Excessive alcohol consumption can adversely affect every organ in the body. There is evidence that chronic consumption increase the risk of upper respiratory and upper digestive tract malignancies and breast cancer.
Human Molecular Genetics, 2008
Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. There were study-wide significant associations (P < 2.3 3 10 24 ) between ADH1B-Arg48His (rs1229984) and flushing and consumption, but only nominally significant associations (P < 0.01) with dependence. Individuals carrying the rs1229984 G-allele (48Arg) reported a lower prevalence of flushing after alcohol (P 5 8.2 3 10 27 ), consumed alcohol on more occasions (P 5 2.7 3 10 26 ), had a higher maximum number of alcoholic drinks in a single day (P 5 2.7 3 10 26 ) and a higher overall alcohol consumption (P 5 8.9 3 10 28 ) in the previous year than those with the less common A-allele (48His). After controlling for rs1229984, an independent association was observed between rs1042026 (ADH1B) and alcohol intake (P 5 4.7 3 10 25 ) and suggestive associations (P < 0.001) between alcohol consumption phenotypes and rs1693482 (ADH1C), rs1230165 (ADH5) and rs3762894 (ADH4). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with AD measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B-Arg48His polymorphism affects both alcohol-related flushing in Europeans and alcohol intake. The absence of study-wide significant effects on AD results from the low P-value required when testing multiple single nucleotide polymorphisms and phenotypes.