Long-lost CMAH gene could be responsible for humans’ predisposition to CVD

A gene wiped out by evolution a few million years ago might be the culprit behind humans’ apparent predisposition to heart disease, researchers at the University of California, San Diego School of Medicine have found.

A decade ago, UCSD's Nissi Varki, MD, and Ajit Varki, MD, noted that naturally occurring coronary heart attacks due to atherosclerosis—the cause of one-third of human CVD deaths today—were virtually nonexistent in other animals, including chimpanzees closely related to humans. Even in chimps with human-like risk factors such as hyperlipidemia, hypertension and physical inactivity, heart attacks were the result of a kind of scarring of the heart muscle that scientists still struggle to make sense of.

Building on those initial findings, the Varkis and colleagues in California published research July 22 in PNAS backing the idea that the evolutionary elimination of a gene known as CMAH might be responsible for humans’ elevated risk for CVD. CMAH produces a sialic acid sugar molecule called Neu5Gc, and in their latest study, mice modified to be Neu5Gc-deficient showed a significant increase in atherogenesis compared to control rodents.

In the study, the Vartis and co-authors postulated a mutation might have inactivated the CMAH gene several million years ago in our hominin ancestors, possibly as the result of a malarial parasite. Their CMAH- and Neu5Gc-deficient mice saw an almost twofold increase in severity of atherosclerosis compared to unmodified mice.

“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 said in a 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.”

Red meat consumption did seem to exacerbate heart disease, though, since Neu5Gc can be found in red meat products. Human-like mice who lacked the CMAH gene and were fed high-fat, Neu5Gc-rich diets in the study experienced a subsequent 2.4-fold increase in atherosclerosis that couldn’t be explained by shifts in blood fats or sugars.

The Vartis et al. said they also noted other physiological changes associated with the evolutionary loss of the CMAH gene, including reduced human fertility and an enhanced ability to run long distances.

“The human evolutionary loss of CMAH likely contributes to a predisposition to atherosclerosis by both intrinsic and extrinsic factors, and future studies could consider using this more human-like model,” the authors wrote in PNAS.