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Why ALDH2 gene variant behind alcohol flush raises heart disease risk

A gene variant that causes the “alcohol flush” reaction increases the risk of heart disease by causing inflammation of blood vessels, especially in drinkers


25 January 2023

Wine bottle and wine Glass

People with the ALDH2*2 gene variant have difficulty metabolising alcohol

Shutterstock/Fenea Silviu

Around 8 per cent of the world’s population has a gene variant called ALDH2*2 that impairs the body’s ability to metabolise alcohol and causes unpleasant symptoms such as flushing soon after people drink. Now, researchers have shown why this mutation also raises the risk of heart disease.

“We are trying to understand why ALDH2*2 is associated with a higher risk of coronary artery disease at a cellular level,” says Hongchao Guo at Stanford University in California.

The ALDH2 gene encodes one version of the enzyme alcohol dehydrogenase, which breaks down the toxic acetaldehydes produced when alcohol is metabolised, and also mops up other harmful substances known as free radicals.

The ALDH2*2 mutation stops the enzyme working. People with this mutation have an increased risk of many conditions, including heart disease, diabetes and various cancers. Why the variant increases the risk of heart disease hasn’t been clear.

Guo and his colleagues first analysed data from biobanks in Japan and UK. They found that the risk of heart disease is four times higher in regular drinkers with ALDH2*2.

In volunteers, they then measured the ability of blood vessels to dilate, using a device called EndoPAT. In people with the ALDH2 gene, this measure increases after drinking, but in those with ALDH2*2, it falls. This may seem odd given that people with ALDH2*2 flush when they drink, but the flushing is caused by the release of histamines, says Joseph Wu, part of the team at Stanford.

Next, they created human stem cells with the ALDH2*2 variant, and derived endothelial cells from them – the type of cells that line blood vessels. They found that the ALDH2*2 cells had higher levels of free radicals and inflammation than normal endothelial cells, and were also less able to generate nitric oxide, which helps relax blood vessels. All these effects were exacerbated by exposing cells to alcohol.

The gene variant also impairs the growth of new blood vessels. “That means that when there is a heart attack, when there is a need of blood vessel growth, carriers have less ability to generate new blood vessels,” says Guo.

The team found that an existing diabetes drug called empagliflozin may reduce these harmful effects in people with ALDH2*2 who drink a lot of alcohol. But for Wu, the take-home message is clear. “If you’re missing this enzyme, try not to drink,” he says. “If you drink consistently, you are at much higher risk of heart disease, hypertension, diabetes and cancer.”

Given its many negative consequences, there has been debate about why this mutation spread and became common, today being found in more than a third of people of east Asian origin.

“My only explanation is that if you are missing this enzyme, you tend to drink less and there’s therefore less chance of you becoming alcoholic,” says Wu.

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More on these topics:

Source link A recent study published in the scientific journal Human Molecular Genetics has found strong evidence of a correlation between the Alcohol Dehydrogenase 2 (ALDH2) gene variant and an increased risk of heart disease. This gene, commonly referred to as the Alcohol Flush Reaction gene, determines whether people experience facial flushing and other physical reactions when they drink alcohol.

The ALDH2 gene is known to vary based on racial background, with East Asians having a high frequency of variants. The study found that people with a variant of this gene were significantly more likely to have coronary heart disease, as compared to those without it. They were also more likely to have stroke, coronary artery calcification, and other cardiovascular risk factors.

The exact mechanism by which this gene increases the risk of heart disease is unknown. However, scientists speculate that its effects may be due to the higher amounts of acetaldehyde, a chemical related to alcohol consumption, that are produced by people with the variant. Studies suggest that the presence of acetaldehyde can cause damage to arteries, resulting in arteriosclerosis, a condition that increases the risk of heart attack and stroke.

Additionally, alcohol consumption is known to increase oxidative stress, a process that leads to cellular damage. Since those with the ALDH2 variant are more likely to experience the physical symptoms of a hangover, they may be at a higher risk of developing chronic health problems due to the increased consumption of alcohol.

The findings of this study are significant in that they provide further evidence of the importance of controlling alcohol consumption. The researchers suggest that it would be beneficial for individuals with this gene variant to practice alcohol moderation, and to become informed of the specific risks associated with their condition. Furthermore, they recommend that governments and other institutions consider this genetic risk when formulating policies and initiating educational interventions.

In conclusion, the ALDH2 gene variant appears to be associated with increased risks of coronary heart disease and other cardiovascular problems. More research is needed to ascertain the exact mechanism by which this gene increases the risk, as well as how it interacts with other genetic and environmental factors. In the meantime, it is important for individuals to be aware of the risks associated with this variant, and to take all necessary steps to reduce their likelihood of developing a related disorder.

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