Independent of cholesterol, gene variants raise risk of heart disease, diabetes, high blood pressure

Risk of Heart Disease

High cholesterol is the most commonly understood cause of atherosclerosis, which is a hardening of the arteries that raises the risk of heart attack and stroke. Heart attack and stroke are the #1 and #5 cause of deaths in the world. Now, a new study led by scientists at Washington University School of Medicine in St. Louis have identified a gene that likely plays a causal role in the coronary artery disease. Furthermore, this newly identified gene acts independently of cholesterol levels. The gene also likely plays a role in related cardiovascular diseases, high pressure, and diabetes.

The new study appears in the March 24 in the journal Science Translational Medicine. Studying mice and the genetic data from humans, the scientists and researchers found the gene – called SVEP1 – makes a protein that drives the development of plaque in the arteries. In mice, the animals missing one copy of the SVEP1 had less plaque in the arteries than the animals with both copies. The scientists and researchers also selectively reduced the protein in the arterial walls of the mice, which led to a further reduction of the risk of atherosclerosis.

Further evaluation of human genetic data, the scientists and researchers found that a genetic variation influenced the levels of the protein in the body also correlated with the risk of developing the plaque in the arteries. Genetically determined levels of the protein meant higher risk of plaque development and vice versa.

Similarly, they found higher levels of the protein correlated with high risk of diabetes and higher blood pressure readings. 

Cardiovascular disease remains the most common cause of death worldwide,” said cardiologist Nathan O. Stitziel, MD, Ph.D., an associate professor of medicine and of genetics. “A major goal of treatment for cardiovascular disease has appropriately been focused on lowering cholesterol levels. But there must be causes of cardiovascular disease that are not related to cholesterol—or lipids—in the blood. We can decrease cholesterol to very low levels, and some people still harbor residual risk of future coronary artery disease events. We’re trying to understand what else is going on, so we can improve that as well.”

The scientists and researchers, including including co-first authors In-Hyuk Jung, Ph.D., a staff scientist, and Jared S. Elenbaas, a doctoral student in Stitziel’s lab, further showed that this protein is a complex structural molecule and is manufactured by vascular smooth muscle cells, which are the cells in the walls of the blood vessels that contract and relax. The protein was shown to drive inflammation in the plaques in the artery walls and to make the plaques less stable. Unstable plaque is particularly dangerous because it can break loose, leading to the formation of a blood clot, which can cause heart attack or stroke

“In animal models, we found that the protein induced atherosclerosis and promoted unstable plaque,” Jung said. “We also saw that it increased the number of inflammatory immune cells in the plaque and decreased collagen, which serves a stabilizing function in plaques.”

According to Stitziel, other genes have previously been identified as contributing the risk of cardiovascular diseases independent of cholesterol. These previously identified genes appear to have a widespread roles in the body and are therefore more likely to have far-reaching and undesirable side effects if blocked in a effort to prevent cardiovascular diseases. Although SVEP1 is required for early development in an embryo, eliminated the protein in adult mice did not appear to be detrimental, according to the researchers.

“The human genetic data showed a naturally occurring wide range of this protein in the general population, suggesting that we might be able to alter its levels in a safe way and potentially decrease coronary artery disease,” Elenbaas said.

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