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Regardless of cholesterol, gene variants increase the risk of heart disease, diabetes and high blood pressure
In-Hyuk Jung, PhD, Stitziel Lab
High cholesterol is the most commonly understood cause of atherosclerosis, a hardening of the arteries that increases the risk of heart attack and stroke. Now scientists at the Washington University School of Medicine in St. Louis have identified a gene that is likely to play a causal role in coronary artery disease, regardless of cholesterol levels. The gene likely plays a role in related cardiovascular diseases, including high blood pressure and diabetes.
The study appears on March 24 in the journal Science Translational Medicine.
While studying mice and human genetic data, the researchers found that the gene – called SVEP1 – makes a protein that drives plaque development in arteries. In mice, animals lacking one copy of SVEP1 had less plaque in the arteries than mice with both copies. The researchers also selectively reduced the protein in the arterial walls of mice, which further reduced the risk of atherosclerosis.
When analyzing the genetic data in humans, the researchers found that the genetic variation that affects levels of this protein in the body correlates with the risk of developing plaque in the arteries. Genetically determined high protein levels meant a higher risk of plaque development and vice versa. Similarly, they found higher protein levels, which correlated with a higher risk of diabetes and higher blood pressure levels.
“Cardiovascular disease remains the leading cause of death worldwide,” said cardiologist Nathan O. Stitziel, MD, PhD, associate professor of medicine and genetics. “A major goal of treating cardiovascular disease has been to lower cholesterol. However, there must be causes of cardiovascular disease that are not related to cholesterol or lipids in the blood. We can bring cholesterol down to very low levels, and some people are still at risk of future coronary heart disease events. We try to understand what else is going on so we can improve that too. “
This is not the first identified non-lipid gene implicated in cardiovascular disease. The exciting aspect of this discovery, however, is that the researchers believe that it is better suited to developing future therapies.
The researchers – including co-first authors In-Hyuk Jung, PhD, a staff scientist, and Jared S. Elenbaas, a graduate student in Stitziel’s laboratory – also showed that this protein is a complex structural molecule and is made by vascular smooth muscle cells that are cells in the walls of blood vessels, which contract and relax the vasculature. The protein has been shown to cause inflammation in the plaques in the arterial walls and make the plaques less stable. Unstable plaque is especially dangerous because it can loosen and lead to the formation of a blood clot, which can cause a heart attack or stroke.
“In animal models, we found that the protein induced atherosclerosis and promoted unstable plaque,” said Jung. “We have also seen that it increases the number of inflammatory immune cells in plaque and decreases collagen, which has a stabilizing function in plaques.”
According to Stitziel, other genes previously found to increase the risk of cardiovascular disease regardless of cholesterol seem to play a widespread role in the body and are therefore more likely to have widespread undesirable side effects when blocked to the heart – prevent circulatory diseases. Although SVEP1 is required for the early development of the embryo, the elimination of the protein in adult mice did not appear to be harmful, according to the researchers.
“Human genetic data showed a naturally occurring broad spectrum of this protein in the general population, suggesting that we may be able to safely change its levels and potentially reduce coronary artery disease,” Elenbaas said.
On-going work in Stitziel’s group is focused on finding ways to block or lower the protein in order to identify new compounds or potential treatments for coronary artery disease and possibly high blood pressure and diabetes. The researchers worked with Washington University’s Office of Technology Management (OTM) to file a patent for therapies that target the SVEP1 protein.
This work was supported in part by National Institutes of Health (NIH) grants, grant numbers T32GM007200, T32HL134635, T32HL007081, R01HL53325, R01HL131961, UM1HG008853, and UL1TR002345; a National Lipid Association career award; and by the Foundation for the Barnes-Jewish Hospital.
Jung I, Elenbaas JS et al. SVEP1 is a human coronary artery disease site that promotes atherosclerosis. Scientific translational medicine. March 24, 2021.
The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and is among the top 10 medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.