Two papers published in the New England Journal of Medicine offer new genetic evidence to support the increasingly accepted though still controversial view that triglycerides play an important causal role in cardiovascular disease. If fully validated the new findings could lead to new drugs to prevent and treat cardiovascular disease, though others caution that there is still a long way to go before this could happen.
Both studies describe the impact of genetic mutations on a gene (ANGPTL4) which encodes for a protein (angiopoietin-like 4) that inhibits lipoprotein lipase, an enzyme that plays a key role in breaking down and removing triglycerides from the blood. The large studies found that people with mutations that inactivate ANGPTL4 have lower levels of triglycerides, higher levels of HDL cholesterol, and decreased risk for cardiovascular disease.
The findings, writes Sander Kersten (Wageningen University, the Netherlands) in an accompanying editorial, “suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.” The studies also “implicate targeted inactivation of ANGPTL4 as a potential weapon in the war on heart disease,” though he also points to a previous study that did not support this hypothesis. Sekar Kathiresan (Broad Institute), senior author of one of the NEJM studies, told me that the previous study was small and “basically got the result wrong. Between, the two papers in this NEJM issue, we are looking at 10X more data.”
Recent large genetic studies have resulted in an important change in the field. Many researchers now believe that HDL, which was once thought to play an important protective role in atherosclerosis, is only a marker of disease. In contrast, triglycerides are now thought by many to play an important functional role.
One of the NEJM papers showed that a human monoclonal antibody to ANGPTL4 lowered triglyceride levels in animals. The study was funded by Regeneron and was performed by researchers at Regeneron and Geisinger, as part of an ongoing collaboration using deidentified genetic data from Geisinger patients. In their NEJM paper the researchers reported inflammation and other side effects in the animals treated with the antibody, but they said that no such problem has been observed in humans who have mutations that have the same functional effect as the antibody.
An important caveat to this research is that it is still very early. Most promising therapeutic targets do not work out. James Stein (University of Wisconsin) praised the papers but also offered a word of caution. “This is great science and important research that sheds light on the genetic regulation of TG-rich lipoproteins, serum TG levels, and CVD risk,” he said. “Since it is hard, if not impossible, to disconnect TG-rich lipoproteins from LDL, we should be humble in extrapolating these findings to clinical medicine in an era of low LDL due to statins and PCSK9 inhibitors. I hope this research identifies new targets for drug therapy and better understanding of CVD risk prediction– only time will tell.”
Previous studies with fibrates and other drugs have failed to convincingly show that lowering triglycerides is beneficial. Kathiresan said that what really seems to matter is “how you alter the plasma triglyceride-rich lipoproteins (TRLs).” Some genes that alter TRLs have other metabolic effects. As an example he cited a gene that lowers TRLs but increases the risk for type 2 diabetes. The NEJM papers, by observing the effect of specific mutations, therefore point the way to targets that may be clinically significant.