Drinking alcohol and getting red on the face! Is the "Asian flush" an evolutionary "defect"?

Leviathan Press:

Do you get flushed when you drink alcohol? This reaction, called alcohol flush, is common among East Asians: about 30% to 50% of Chinese, Japanese and Koreans experience this physiological reaction after drinking, including facial flushing, nausea, headache and tachycardia. So it is also called "Asian flush".

For these people, alcohol is definitely not a pleasant experience. Now we know that this reaction is caused by the ALDH2*2 gene in the body, which weakens the function of acetaldehyde dehydrogenase to break down acetaldehyde. This sounds like some kind of evolutionary "defect", but is it really the case?

At every party, no matter the occasion, my drink of choice is soda and lime. I have never been drunk or even finished a full glass of wine. The only time I came close to being drunk (half a glass of mulled wine), my heart rate started to soar, the room was spinning, and my face became red and hot... all of which happened after an academic event when I fainted in front of a university professor.

My aversion to alcohol can be traced entirely to my genes: like approximately 500 million people worldwide (most of whom are East Asians), I carry a genetic mutation called ALDH2*2, which causes me to produce an enzyme called aldehyde dehydrogenase 2, preventing my body from properly breaking down the toxic components of alcohol[1].

As a result, every time I drank, various toxins called acetaldehydes accumulated in my body—a plight that was communicated to everyone around me through my face.

© Refinery29

Evolutionary logic suggests that I and other people with so-called “alcohol flushes” (also known as Asian flushes) should not exist. Alcohol isn’t the only source of acetaldehyde in the body. Our own cells naturally produce these compounds, and if they’re not cleared away quickly, they can wreak all sorts of havoc on our DNA and proteins.[2]

So even at baseline, alcoholics carry extra toxins that make them more susceptible to a host of health problems, including esophageal cancer and heart disease. Yet, somehow, our group of people with this heavy genetic baggage has grown to 500 million in just 2,000 years.[3]

The reason may have to do with a different evolutionary logic - not because acetaldehyde is harmful to us, but because of the harm it may cause to some of our tiny enemies.

As New York University microbiologist Heran Darwin and colleagues pointed out in a conference report, people with the ALDH2*2 mutation may be particularly good at fighting certain pathogens , including the bacterium that causes tuberculosis, one of the deadliest infectious diseases in recent history.

© Sunset Alcohol Flush Support

The study is currently under review in the journal Science and has not yet been fully reviewed by other scientists.[4] It may be difficult to truly determine whether tuberculosis or any other pathogen was the evolutionary catalyst for the increase in ALDH2*2 mutations.

But if infectious disease explains in part the staggering size of the alcohol flush group—as several experts told me it likely is—then the mystery of one of the most common mutations in humans would be close to being solved.

Scientists have long been aware of the adverse effects of aldehydes on DNA and proteins. Ketan J. Patel, a molecular biologist at the University of Oxford who studies the ALDH2*2 mutation and is reviewing the new research for publication in the journal Science, says these compounds are actually carcinogens that “damage the fabric of life.”[5]

Yet for years, many researchers have viewed these chemicals as nasty, everyday garbage from our bodies. Our bodies produce them during normal metabolism. These compounds can also accumulate during infection or inflammation as a byproduct of some of the toxic chemicals we produce. But aldehydes are usually cleared away by our cleansing systems, like so much microscopic garbage.

© South China Morning Post

Darwin and her colleagues are now convinced that these chemicals deserve more credit.[6]

Adding aldehydes to laboratory cultures kills tuberculosis bacteria within days. In previous studies, Darwin’s team has also found that aldehydes, including those produced by the bacteria themselves, can make tuberculosis bacteria extremely sensitive to nitric oxide (a defensive compound produced by the body during infection) and copper (a metal that destroys many microorganisms on contact).[7][8] (It’s worth noting that the aldehydes produced in our bodies after we consume alcohol don’t seem to have much effect on tuberculosis bacteria, Darwin told me. In fact, drinking alcohol has actually been linked to worsening of the disease.)

The team is still summarizing the many ways aldehydes exert their antimicrobial effects. Darwin suspected that bacteria sensitive to these chemicals died a “death by a thousand cuts.” This made aldehydes less of a worthless waste product. Perhaps our ancestors’ bodies realized the universal destructive power of these molecules and began to consciously use them in their own defenses.

“The immune system exploits this toxicity,” says Joshua Woodward, a microbiologist at the University of Washington who has studied the antimicrobial effects of aldehydes.[9]

© VOX

Specific cells show that they are aware of the powerful effects of aldehydes. Sarah Stanley, a microbiologist and immunologist at the University of California, Berkeley, who co-led the study with Darwin, found that when immune cells receive certain chemical signals that indicate infection, they enhance some metabolic pathways that produce aldehydes. Researchers recently found that these same signals can also prompt immune cells to reduce levels of aldehyde dehydrogenase 2, the acetaldehyde-detoxifying enzyme that people like me cannot produce normally due to the mutant gene.

If tweaking the enzyme is a way for cells to increase their supply of toxins in preparation for an inevitable attack, this could be good news for people with the ALDH2*2 gene, who have trouble making enough of the enzyme. When the researchers deleted the ALDH2 gene in mice and then infected them with tuberculosis, they found that the mice had fewer bacteria accumulating in their lungs.

The buildup of aldehydes in the mutant mice wasn’t enough to render them completely immune to TB, but even a small boost in defense could be a big advantage in the fight against the deadly disease, Russell Vance, an immunologist at the University of California, Berkeley, who has been collaborating with Darwin and Stanley on the project, told me. Darwin is now curious whether TB’s aversion to acetaldehyde could be exploited during infection, perhaps by adding antabuse (disulfiram), a drug that blocks aldehyde dehydrogenase, mimicking the effects of ALDH2*2, to a course of antibiotics.

Several experts told me that it was a big leap to link these results to the presence of ALDH2*2 in 500 million people. Here are some relevant clues: Darwin and Stanley’s team found that in a group of people from Vietnam and Singapore, people with this mutation were less likely to develop active cases of tuberculosis, which echoes a pattern documented by at least one other study from South Korea. [10]

But Daniela Brites, an evolutionary geneticist at the Swiss Tropical and Public Health Institute, told me that the link still feels a little uncertain. She noted that other studies looking for genetic susceptibility or resistance to tuberculosis have not implicated ALDH2*2 — suggesting that any link is likely to be weak.

© Paul Spella

The team’s overall idea may still work. “They’re definitely on the right track,” Patel told me. For much of human history, infectious disease has been one of the most significant factors in life and death, a stress so great that it has left a visible mark on the human genome. In some parts of the African continent, a mutation that predisposes to sickle-cell anemia became so common that it helped protect people from malaria.

Patel says the situation with ALDH2*2 may be similar. He believes that some infectious agent, perhaps several, plays an important role in maintaining the mutation. Tuberculosis, with its devastating history, could be one of them, but it may not be the only one.

A few years ago, research from Woodward’s lab showed that aldehydes also affect bacterial pathogens such as Staphylococcus aureus and Francisella novicida.[11] (Darwin and Stanley’s teams have now shown that mice lacking ALDH2 are more resistant to the closely related bacteria, F. tularensis.) Che-Hong Chen, a geneticist at Stanford University who has studied ALDH2*2 for years, thinks the culprit may not be bacteria at all. He prefers the idea that it could once again be malaria, which operates in a different part of our genome, in a different part of the world.

Other minor benefits of ALDH2*2 may help the mutation spread. As Chen points out, it’s a pretty big disincentive to drinking — and people who abstain from alcohol (which, of course, isn’t the case for all of us) do avoid many potential liver problems.

This is also the good news that comes with my genetic abnormality, even if it seems more troublesome at first glance.

References:

[1]pubmed.ncbi.nlm.nih.gov/35749303/

[2]www.nature.com/articles/nature25154

[3]www.nature.com/articles/s41467-018-03274-0

[4]www.biorxiv.org/content/10.1101/2023.08.24.554661v2

[5]monographs.iarc.who.int/agents-classified-by-the-iarc/

[6]royalsocietypublishing.org/doi/pdf/10.1098/rsob.220010

[7]www.cell.com/molecular-cell/fulltext/S1097-2765(15)00047-7

[8]journals.asm.org/doi/10.1128/mbio.00363-23

[9]elifesciences.org/articles/59295

[10]www.ncbi.nlm.nih.gov/pmc/articles/PMC3975138/

[11]elifesciences.org/articles/59295

By Katherine J. Wu

Translated by tamiya2

Proofreading/Rabbit's Light Footsteps

Original article/www.theatlantic.com/science/archive/2023/10/alcohol-flush-asian-genetic-mutation-cause/675759/

This article is based on the Creative Commons License (BY-NC) and is published by tamiya2 on Leviathan

The article only reflects the author's views and does not necessarily represent the position of Leviathan