Toward a complete genetic picture of heart disease

Broad-led team reveals new genetic findings that link major pathway for triglyceride metabolism to risk of coronary artery disease

For decades, scientists have searched for the biological roots of coronary artery disease (CAD), the most common form of heart disease and the leading cause of death in the United States. LDL, a type of fat in the blood, emerged early on as a key player — high levels raise the risk of CAD and heart attack. Based on these insights, LDL-lowering drugs were first introduced in the late 1980’s and are now a staple of modern medicine.

There are other types of fat in the blood, too, but the data on these have been murkier, leading to conflicting views about their roles in CAD. Over the past several years, Sekar Kathiresan, an institute member at the Broad Institute and director of the Broad Cardiovascular Initiative, has harnessed the tools of the human genome to bring clarity to this area. In particular, he and his colleagues recently identified a handful of genes that function in a previously overlooked pathway for clearing triglyceride-rich lipoproteins (TGs) from the blood, which has refocused attention on TGs as a causal factor in CAD. Now, Kathiresan’s latest work, appearing in the March second issue of The New England Journal of Medicine, directly implicates two more genes in this same pathway — known as the lipoprotein lipase (LPL) pathway — providing robust evidence that lowering TG levels through this pathway can lower the risk of CAD.

“The real takeaway from our work is that the LPL pathway is a major player,” said Kathiresan, who is one of four senior authors on the new NEJM study and also the director of preventive cardiology at Massachusetts General Hospital. “Beyond LDL, the LPL pathway is a key route to higher blood lipids and increased risk for coronary artery disease. It’s now crystal clear.”

Two studies published in 2014 (one in NEJM and the other in Nature) provided some of the earliest genetic evidence that TGs are indeed an important risk factor in heart disease. Those studies identified two genes, APOC3 and APOA5, both of which regulate LPL.

In the latest study, Kathiresan and his colleague Nathan Stitziel, then a postdoc is his laboratory, sought to enhance this genetic picture. Together with collaborators across the U.S. and the globe, the researchers set out to analyze genetic variants that reside in the protein-coding portion of the genome (known as the “exome”). Their exome emphasis is a practical matter: Although the vast majority of the human genome does not encode proteins, the functional significance of these non-coding, non-exome regions remains largely unclear.

The team analyzed the exomes of nearly 200,000 people (with and without CAD) using techniques that capture both common and rare genetic variation. A significant source of funding for the work came from the National Human Genome Research Institute (NHGRI), which recently renewed its support for the Broad’s large-scale genome sequencing efforts under a new program focused on the genomics of common diseases.

Kathiresan, Stitziel, and their colleagues uncovered genes that have already been linked to CAD, including PCSK9. About a decade ago, mutations that disable this gene were found to protect against the disease and also lower LDL. Drugs that target PCSK9 were just approved last summer after clinical trials revealed they can lower LDL levels when combined with statins.

Notably, the group also turned up some new finds. They identified mutations in the gene ANGPTL4 (angiopoietin-like 4) that disrupt its function and also protect against CAD. Importantly, people carrying these disabling mutations also had lower TG levels — roughly 35% lower than people without the mutations.

Another important clue came from the biological role of ANGPTL4: it inhibits LPL. So, the researchers wondered if they could also find mutations in the LPL gene. Indeed, they did. Mutations that inactivate LPL are associated with an increased risk of CAD, while those that ramp up its activity appear to protect against the disease.

“We’ve now identified a series of genes that are all triglyceride-regulating genes, and they all affect risk of coronary artery disease,” said Kathiresan. “What’s really amazing is that all these genes are connected, either LPL or ones that regulate the function of LPL.”

Through large, unbiased surveys of the human genome, Kathiresan and his colleagues have contributed fundamental genetic insights that underscore the role of TGs in heart disease risk. Moreover, their work also points the way to novel therapies aimed at lowering TG levels.

“We now have very effective medicines to lower LDL cholesterol,” says Kathiresan. “What we need to do now is find effective interventions (medicines or lifestyle) that address this pathway and reduce risk for coronary heart disease.”

In their latest NEJM study, the researchers also reveal another gene, called SVEP1, which is significantly associated with CAD. Interestingly, the gene does not appear to track with any fats in the blood, but seems to be linked with blood pressure. Additional studies are required to sort out the biology behind its connection to heart disease.

This work was made possible by a broad international collaboration led by researchers at multiple institutions, including the Broad Institute, Massachusetts General Hospital, Washington University School of Medicine, Queen Mary University of London, University of Leicester, and the German Heart Center, Munich.

Paper cited:

The Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Artery Disease. NEJM. March 2, 2016. DOI: 10.1056/NEJMoa1507652