Gene Mutation Could Explain Humans’ High Risk of Heart Attack
Gene Mutation Could Explain Humans’ High Risk of Heart Attack

Gene Mutation Could Explain Humans’ High Risk of Heart Attack

Mutating a gene called CMAH in mice so it’s nonfunctional, as in humans, upped the animals’ chances of developing heart disease, a study finds.

Shawna Williams
Jul 23, 2019


Between 2 million and 3 million years ago, humans lost the function of a gene called CMAH, one that remains active in other primates today. The mutation likely spread through our human ancestors because it has some benefit. For example, it’s thought to make humans better long-distance runners than our evolutionary cousins. But a new study in mice points to a significant downside: A far higher risk of heart attack.

Heart disease is the most common cause of death in the US, and atherosclerosis—the buildup of plaque on the inside of arteries—is frequently a component of that disease. Yet atherosclerosis isn’t a problem for other apes, even captive animals subject to some of the same risk factors as humans, such as high blood pressure and physical inactivity, Nissi Varki and Ajit Varki of the University of California, San Diego (UCSD), have found in previous work. “That’s always been a puzzle,” Ajit Varki tells The Guardian. “What’s unusual about humans?” 

In their new study, published yesterday (July 22) in PNAS, the Varkis and their collaborators compared mice modified to have a human-like deficiency in the CMAH gene with mice without the mutation. When fed a high-fat diet, the animals with the mutation had an incidence of atherosclerosis that was 1.9 times higher than that of the controls, the researchers report.

CMAH codes for an enzyme that generates a sialic acid known as Neu5Gc. The UCSD team says the loss of Neu5Gc raises the risk for heart disease in two ways: it increases the susceptibility to atherosclerosis and it makes the immune system treat Neu5Gc as a foreign molecule when it’s ingested in meat, leading to inflammation.

“The increased risk appears to be driven by multiple factors, including hyperactive white cells and a tendency to diabetes in the human-like mice,” Ajit Varki says in a university press release. “This may help explain why even vegetarian humans without any other obvious cardiovascular risk factors are still very prone to heart attacks and strokes, while other evolutionary relatives are not.”

Jake Lusis of the University of California, Los Angeles, who was not involved in the study, writes in an email to The Morning Call that it convincingly makes the case that the CMAH mutation is a human-specific risk factor for atherosclerosis. “It should be noted, however, that this is one of hundreds of factors contributing to the disease, and its relative importance is still unclear,” he adds.

Dorian Haskard of Imperial College London similarly praised the study in an interview with The Guardian, while cautioning against inferring too much based on the results. “The changes seen in a mouse may be very different from those in a human,” he says. “In a mouse study, the disease is greatly accelerated, so there needs to be much more work done on the association with humans.”

Shawna Williams is an associate editor at The Scientist. Email her at