The ADH1B*3 allele may also increase the risk for liver disease if individuals choose to drink

* Alcohol dehydrogenase (ADH) is one of the major enzymes involved in alcohol metabolism.

* New findings indicate that the ADH1B*3 allele may protect against the development of alcoholism.

* At the same time, the ADH1B*3 allele may be a risk factor for liver disease most likely because it increases levels of acetaldehyde if an individual with the allele does drink.

Alcohol dehydrogenase (ADH) is one of the major enzymes involved in alcohol metabolism. The genes for ADH are polymorphic at two loci, ADH1B and ADH1C. While the three alleles at the ADH1B locus have previously been linked with protection from alcohol dependence, a new study is the first to examine the relationship between the ADH1B*3 allele and alcohol-related disorders among Afro-Trinidadians. Findings indicate that while the ADH1B*3 allele appears to protect against alcoholism, it can also increase the risk for liver disease among those individuals who drink heavily.

Results are published in the February issue of Alcoholism: Clinical & Experimental Research.

"Alcohol is primarily metabolized or broken down in the liver by two enzymes," explained Cindy L. Ehlers, associate professor of molecular and integrative neuroscience at The Scripps Research Institute. "The first is ADH, which converts alcohol to acetaldehyde. Acetaldehyde is a toxic compound that can be damaging to the liver and other body organ systems. The second enzyme is aldehyde dehydrogenase (ALDH), which breaks down acetaldehyde to acetate, a relatively nontoxic compound."

Ehlers said that most people do not realize that people of different racial origins metabolize alcohol differently and that this influences their risk for alcoholism. "Approximately 40 percent of Asians have a mutation in ALDH that may cause them to have an aversive reaction when they drink so they are much less likely to develop alcohol dependence." And recently, she said, researchers have discovered that individuals of African ancestry have a form of ADH that is more active.

"These same authors have shown that young African Americans with the ADH1B*3 allele tend to have a more intense response to alcohol, and are less likely to have a positive family history of alcoholism - both of which are associated with a reduced vulnerability for the development of alcohol-use disorders," said Mary-Anne Enoch, a staff scientist in the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism. "This current study builds on those earlier studies."

"Although ADH1B*3 was identified in Indianapolis 10 years ago, there had been few studies that investigated its role in drinking or the development of alcoholism," said Ehlers. "Trinidad and Tobago is an island nation in the Caribbean comprised mainly of individuals of two separate ethnic groups of African and East Indian ancestry. Island populations often provide a unique opportunity to evaluate genetic factors as populations on these islands are often genetically 'isolated' for a number of generations and can have a more homogenous environment when compared to large heterogeneous cultures such as the United States."

Study participants were recruited from the two major ethnic groups of Trinidad: 138 alcohol-dependent individuals, as well as 98 "controls" or non-alcohol-dependent individuals matched on age, gender, education, and ethnicity. Researchers assessed all participants using the Semi-Structured Assessment for the Genetics of Alcoholism in order to gather information on demographics, psychiatric diagnoses, personal drinking, and drug-use history. Each participant was genotyped at the ADH1B locus through a blood sample, and also provided a number of other health measures.

"As predicted, we found a relatively high prevalence of the ADH1B*3 allele - a full 41 percent - in Afro-Trinidadians," said Ehlers. "Individuals with at least one ADH1B*3 allele were found to have lower alcohol consumption levels and were less likely to be alcohol dependent. Thus, we have found that this allele is protective against the development of alcoholism."

However, the ADH1B*3 allele may also be a risk factor for liver disease. "Elevated serum alanine aminotransferease levels are a measure of liver dysfunction," said Ehlers. "Since having the ADH1B*3 allele presumably causes increases in acetadehyde when an individual drinks, especially at higher levels of consumption, individuals who have this allele and who nonetheless drink heavily could be at higher risk for alcohol/acetaldehyde-induced organ damage."

"These findings are likely to be most significant for African-descent individuals," said Enoch, "around a third to one-half of whom may carry this allele, as this study has shown that they have a reduced risk of developing alcoholism. However, it is important that they should not develop a false sense of security. This study shows that this particular ADH variant may be both protective for addiction and a risk factor for liver disease in African-descent individuals in the same way that another ADH variant, ADH1B*2, is both a protective and risk allele in East Asians."

"We still do not know what causes alcoholism," said Ehlers. "It appears that 50 percent of the disorder is genetic and 50 percent is environmental. Having the ADH1B*3 allele provides some genetic protection from developing alcoholism but it is not complete. Individuals can choose to drink at high levels in spite of having some protection against alcoholism just like individuals at high genetic risk for alcoholism can choose not to drink. There are no genes for alcohol dependence like there are genes for Huntington's chorea or other single-gene disorders. There are only genes that influence risk and protection for the disorder. While there have been a number of studies demonstrating that, overall, African Americans have lower rates of alcohol dependence when compared to EuroAmericans and Native Americans … we have simply isolated one reason why that might be so."



Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Association of the ADH1B*3 Allele with Alcohol Related Phenotypes in Trinidad," were: Karelia Montane-Jaime, Shelly Moore, and Samuel Shafe of the University of the West Indies; Roma Joseph of the San Fernando Hospital in Trinidad; and Lucinda G. Carr of Indiana University. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the Stein Endowment Fund, and the University of the West Indies.

Contact:

Cindy L. Ehlers, Ph.D.
The Scripps Research Institute

Mary-Anne Enoch, M.D.
National Institute on Alcohol Abuse and Alcoholism

Alcoholism: Clinical & Experimental Research