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Colin MacKenzie M.D.
December 26, 2020

Association of Genetic Variants in Alcohol Dehydrogenase 4 with Alcohol Dependence in Brazilian Patients

Introduction

Science has learned a fair bit about specific genes you inherit from your family that may make you more susceptible to alcohol use problems.

The liver enzyme alcohol dehydrogenase 4 (ADH4) plays an important role in alcohol use behavior and the development of alcohol dependence.  In the liver, alcohol is metabolized by this enzyme to acetaldehyde and then further to an acetate using another liver enzyme called aldehyde dehydrogenase (ALDH)

This study examines the genes that code for the ADH enzyme.  The ADH enzyme has many allelic variants (one of several alternative types of the same gene found at a certain location on the chromosome). These enzyme and their genetic variants, (often referred to as polymorphisms) convert alcohol molecules to acetaldehyde at different rates. Think of a polymorphism as like having purple eyes instead of brown eyes.  It’s different but not necessarily abnormal.  It is believed that those people who inherit “faster” enzyme variants have a lower risk of alcohol dependence. 

One version of ADH, called ADH4, is found mainly in the liver, and during alcohol intoxication, can contribute up to 40% of the total metabolism/oxidation rate of ethanol. 

Methods

In this study, the researchers examined three different versions of the ADH gene, specifically a portion of the ADH gene called the “promoter.”  A promoter is a strand of the gene that initiates transcription of the gene (or makes it active). The ADH4 enzyme itself has promotors that are also variable in type. Three different polymorphisms in the ADH4 promoter can be seen: -192 base pair (T/A), -159 base pair (G/A) -75 base pair (A/C). 

The effect of these polymorphisms on gene expression in four different haplotypes (a group of alleles that are transmitted simultaneously) (T,A,C; T,G,A; A,G,C; and T,A,A); are assessed in this study.   An allele is a gene produced by a specific mutation and a haplotype is a set of genes that get passed down usually from one parent as a group. 

Results

Patients with two of the ADH4 polymorphisms, and their associated haplotypes, were associated with a greater risk of developing alcohol dependence than those without these ADH4 polymorphisms.  Specifically, those with a cystine at the -75 base pair and adenine at the -159 base pair of the ADH4 gene polymorphism (partial DNA sequence that determines a specific characteristic of that organism) were three times as likely to have alcohol-dependence compared to non-alcoholic subjects.  These ADH4 polymorphisms inherited by the alcoholic group were much slower enzymes than the ones inherited by the non-alcoholic group and are associated with alcohol use disorders.

Conclusion

This study identified certain types of the ADH4 gene responsible for creating the enzyme that converts ethanol to acetaldehyde.  They discovered that certain types of this gene are more highly associated with alcoholism than other types.  Is it possible that those people who inherit these forms of the ADH4 gene have a higher risk of developing alcoholism?  

References

Guindalini C, Scivoletto S, Ferreira RG, et al. Association of genetic variants in alcohol dehydrogenase 4 with alcohol dependence in Brazilian patients. Am J Psychiatry. 2005;162(5):1005-1007. doi:10.1176/appi.ajp.162.5.1005