A new paper challenges the assumption that raising high-density lipoprotein necessarily lowers the risk of myocardial infarction.
A team led by researchers from the Broad Institute and Massachusetts General Hospital explored naturally occurring genetic variations in humans to test the connection between HDL levels and MI. By studying the genes of roughly 170,000 individuals, the team discovered that, when examined together, the 15 HDL-raising variants they tested do not reduce the risk of MI.
“Its been assumed that if a patient, or group of patients, did something to cause their HDL levels to go up, then you can safely assume that their risk of heart attack will go down,” Sekar Kathiresan, MD, the studys senior author and director of preventive cardiology at MGH, associate professor of medicine at Harvard Medical School and an associate member of the Broad Institute, said in a news release.
“This work fundamentally questions that.”
More than 30 years ago, human epidemiological studies first revealed an association between HDL and risk of MI: the higher the levels, the lower the risk. Experiments in cells and mice have further supported the idea, and suggest that HDL is protective because it may remove cholesterol from the sites where it can cause damage.
However, researchers have struggled to prove conclusively that raising HDL levels is beneficial, according to the news release. Studies of human genetic diseases where individuals have very low HDL levels have not yielded definitive answers as to the impact on MI. And because there currently are no drugs that specifically elevate HDL levels, researchers have had a hard time proving in humans that such an intervention will lower MI risk.
“There are many biomarkers measurable in the blood that track with disease but only a very small number are actually causal and directly participate,” first author Benjamin Voight, who since completing this work has left the Broad Institute and MGH for a position as an assistant professor at University of Pennsylvania, said in the news release. “The reason you want to distinguish between causal and non-causal biomarkers is because of the implications for therapy.”
In the latest study, individuals who carried a particular variation in a gene called endothelial lipase had HDL levels that were elevated about 6 milligrams per deciliter, or 10% — a change expected to decrease MI risk by about 13%, according to the researchers. However, these individuals showed no difference in their risk of heart disease compared to people without the variant.
Similarly, the researchers identified a cohort comprised of 14 different HDL-raising variants. They devised a scoring system based on the total number of copies of the gene variants a person carries — ranging from 0 to 28 — and then asked whether that score relates to the risk of MI. Here also they uncovered no association.
Kathiresan emphasized that these results do not diminish the value of HDL levels as a biomarker that can help estimate a persons likelihood of developing heart disease.
“We know that HDL is a great biomarker — its quite useful in identifying individuals at higher risk of having a heart attack in the future,” Kathiresan said. “But we have shown that you cannot assume that raising HDL by any mechanism will help patients. Perhaps other mechanisms exist that can lower risk, but we will need to keep searching for them.”
The study appeared May 17 on the website of The Lancet. To read the abstract and access the study via subscription or purchase, visit http://bit.ly/J0PoqL.