The loss of a single gene up to three million years ago may explain why humans are at a greater risk of heart disease.
A decade ago scientists discovered homo sapiens are virtually the only animals to suffer heart attacks as a result of plaque accumulating in the arteries.
Our ancestors are thought to have passed down a mutation in the gene CMAH, which has left us unable to produce the cellular-signalling molecule Neu5Gc.
When scientists ‘knocked out’ CMAH in mice, the rodents’ arteries ‘furred up’ almost twice as much as the unmodified animals’ blood vessels.
And eating red meat only heightens the risk, the study also suggests. Lamb, beef and game are rich in Neu5Gc, which our bodies do not recognise.
Feeding Neu5Gc to mice that lacked CMAH increased the plaque in their arteries by 2.4 times. The ‘non-human molecule’ is thought to trigger dangerous inflammation.
A genetic mutation millions of years ago may explain why humans suffer heart attacks (stock)
The research was carried out by the University of California, San Diego, and led by Dr Ajit Varki, distinguished professor of medicine, and cellular and molecular medicine.
One in four deaths in the US and UK occur due to cardiovascular diseases like heart attacks or strokes, statistics show.
Atherosclerosis is a leading cause of these disorders. It is defined as the build-up of plaque in the arteries, which restricts blood flow to the major organs.
If this plaque breaks off and travels elsewhere, known as an embolism, it can further restrict the supply of oxygen-rich blood to the heart and brain.
Obesity, smoking and inactivity all raise the risk of atherosclerosis. However, around 15 per cent of first-time heart attacks or stroke have no obvious cause.
The San-Diego scientists were the first to note humans are the only animals to suffer heart attacks due to atherosclerosis.
‘That’s always been a puzzle,’ Professor Varki said. ‘What’s unusual about humans?,’
Even when our close ‘relatives’ chimpanzees live in captivity and are inactive, their heart attacks are usually caused by scarring of the cardio muscle.
To uncover how effective Neu5Gc is at protecting against heart disease, the researchers genetically engineered mice to not produce the molecule.
These rodents went on to have almost twice as severe atherosclerosis as the animals that still expressed CMAH.
‘The increased risk appears to be driven by multiple factors, including hyperactive white cells and a tendency to diabetes in the human-like mice,’ the authors said.
WHAT IS ATHEROSCLEROSIS?
Atherosclerosis occurs when plaques made of fat, cholesterol, calcium and other substances accumulate in artery walls.
Over time, the blood vessels harden and narrow, which restricts the flow of blood around the body.
When these plaques rupture, they form a blood clot that can further block the flow of oxygen-rich blood.
Atherosclerosis is most serious when it reduces blood supply to the heart or brain, which can result in a heart attack or stroke, respectively.
The condition, and the diseases it can cause, is the single biggest cause of death in the developed world, with it being responsible for one in three fatalities.
Atherosclerosis often starts in childhood and worsens with age, however, most do not experience symptoms until middle age or older.
Risk factors include:
- High blood pressure
- Elevated cholesterol levels
- Poor nutrition
- Excessive alcohol consumption
All the above can damage the thin layer, the endothelium, that keeps the inside of our arteries smooth.
Once damaged, ‘bad’ cholesterol accumulates in the artery wall.
The body sends immune cells to clean up this cholesterol, which can then get stuck in the damaged site.
This causes plaque to build-up over time.
Over production of white blood cells by the immune system can drive inflammation and prevent fatty substances from being cleared from the artery walls.
Perhaps surprisingly, exposure to Neu5Gc in our food could make our heart disease risk worse not better.
Dietary exposure is thought to trigger an immune response and chronic inflammation, which the researchers call xenosialitis.
They compare Neu5Gc in animal products to a ‘Trojan horse’, with the molecule ‘sneaking in and causing an inflammatory immune response’.
In a second part of the experiment, mice that were modified not to express CMAH were fed a high-fat diet rich in Neu5Gc.
This led to a 2.4 increase in atherosclerosis, which could not be explained by a rise in the rodents’ circulating fats or blood-sugar levels.
‘The human evolutionary loss of CMAH likely contributes to a predisposition to atherosclerosis by both intrinsic and extrinsic [dietary] factors,’ the researchers wrote.
They hope to develop an ‘antidote’ that allows people to enjoy moderate amounts of red meat without ‘the negatives’.
Professor Metin Avkiran, associate medical director at the British Heart Foundation, told The Guardian: ‘Learning from naturally-occurring genetic variations is improving our understanding of atherosclerotic disease and powering the development of new treatments.’
Dorian Haskard, professor of cardiovascular medicine and rheumatology at Imperial College London, called the study ‘interesting’ and ‘possibly groundbreaking’.
However, he warned atherosclerosis likely comes on much quicker in mice than humans and therefore the results need to be interpreted with caution.
Dietary exposure to Neu5Gc in mice that lack CMAH has also been linked to inflammation and cancer progression.
This may explain why a high consumption of red meat is associated with certain tumours, the researchers claimed.
However, inactivation of CMAH may not be all bad. The mutation is linked to improved stamina and may help explain why humans can run long distances, they added.
Neu5Gc is a type of sugar called sialic acid. These acids are found on the surface of cells and play a number of roles.
One is to flag our cells as being healthy to the immune system,
Humans’ CMAH mutation is thought to have occurred two-to-three millions years ago.
This may have ‘caught on’ due to a particular strain of the malaria parasite recognising Neu5Gc, they researchers added.
Not producing Neu5Gc would therefore have been an evolutionary advantage at the time.
However, the malaria parasite is said to have evolved to pick up on the sialic acid humans do possess, which is called Neu5Ac.