Why gene variant impairing alcohol breakdown 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

By Michael Le Page

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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