Alcohol Flush: A Genetic Puzzle

On January 27, 2011

For this post, we have a genetic puzzle to discuss concerning alcohol metabolism.

For many markers, two copies of a defective allele is worse than having one copy. For a variant associated with alcohol flush, which is part of Pathway Fit, having two defective alleles makes an individual more sensitive to alcohol flush than one defective allele. However, those same defective alleles show a different pattern with respect to cancer risk. One defective allele increases cancer risk, but two defective alleles lower cancer risk.

How is that possible?

Let’s start by describing alcohol flush. For some of us, drinking red wine or other alcoholic beverages may cause an unpleasant reaction. The face starts to flush red and in some cases feel warm and itchy. Sometimes facial flushing is accompanied by other symptoms, such as rapid heartbeat, nausea, or dizziness.

It turns out that the culprit is a toxic substance called acetaldehyde.

When most people drink alcohol, their bodies break down the alcohol in two steps (PMID 15099407). In the first step, alcohol is converted into acetaldehyde by the enzyme alcohol dehydrogenase (ADH). In the second step, acetaldehyde is further broken down by the enzyme aldehyde dehydrogenase (ALDH2) into acetate, which is cleared from the body after being hydrolyzed into carbon dioxide and water.

Some people have a genetic variant in ALDH2 which renders the enzyme less active (PMID 6117742).  In these people, when they drink alcohol, there is a buildup of acetaldehyde, causing facial flushing and other associated symptoms.

There are two main variants of ALDH2 (PMID 15099407). The ALDH2*1 allele encodes an enzyme with normal ALDH2 activity whereas the ALDH2*2 allele encodes an inactive enzyme. People who have at least one defective *2 allele are more likely to experience alcohol flush than people carrying two copies of the normal *1 allele. Moreover, people with two defective *2 alleles are more likely to have a severe alcohol flush response compared to people with only one *2 allele.

People with alcohol flush who drink alcohol are at high risk of developing esophageal cancer (PMID 19320537).  Acetaldehyde, like alcohol, is listed as a class I carcinogen by the World Health Organization (PMID 19891056).

However, people with only one defective *2 allele (*1/*2 genotype) are at much higher risk of developing esophageal cancer (odds ratio ranging from 3.7 to 18.1) compared to people with no defective alleles (*1/*1 genotype), while people with two defective *2 alleles (*2/*2 genotype) are at a lower risk (PMID 19320537, PMID 16103445, PMID 12672787).  How can that be?

It turns out that people with two copies of the *2 allele are less likely to consume alcohol than people with one copy of the *2 allele, probably due to the unpleasantness of the alcohol flush response (PMID 15542751, PMID 1560668). Indeed, a drug called disulfiram (commonly know by its brand name, Antabuse) that inhibits this enzyme (and thus mimics the *2/*2 genotype) is given to alcoholics to help them overcome addiction (PMID 9354647, PMID 2735956, PMID 16702894). Thus, they are less likely to consume alcohol compared to most people, and accordingly have less exposure to the carcinogenic effects of acetaldehyde and alcohol.

In contrast, while people with the *2/*2 genotype are less likely to drink alcohol, people with only one copy of the *2 allele (*1/*2 genotype) experience a less severe flushing reaction due to residual enzyme activity, and can develop tolerance to increased amounts of alcohol over a period of time. So they are more likely to continue to drink alcohol, and thus, expose themselves to the carcinogenic effects.

Approximately 36% of East Asians (Japanese, Chinese and Koreans) have at least one copy of the *2 allele (PMID 17718397) and experience alcohol flush, which is also called Asian flush or Asian glow. This allele is very rare in Caucasians and Africans. While they also may experience flushing symptoms after alcohol consumption, the underlying mechanisms are still under investigation. Moreover, other genetic variants may play a role in alcohol metabolism in Asians as well as other ethnic groups (PMID 16702384).

In most cases, avoiding alcohol is the best remedy for those of us who experience alcohol flush.  If your Pathway Fit results show that you have a A/G genotype at rs671, then you have the *1/*2 genotype, and drinking alcohol may increase your risk of esophageal cancer.

Flushing that alcohol away might not be that bad an idea after all!

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