Challenging conventional wisdom, researchers assert that the true causal factor in heart disease is not a deficiency of HDL (“good”) cholesterol, but rather an abundance of triglycerides. These researchers point to their recent work exploring the relationship between heart disease, HDL, and triglycerides, which has remained relatively murky, despite the well-known link between heart disease and another kind of circulating fat, LDL (“bad”) cholesterol.

The shift from HDL to triglycerides is not entirely unprecedented. According to several clinical trials and at least one large-scale genetic study, elevated HDL levels do not appear to prevent heart disease. In addition, a genetic study examined the role of common genetic variation in influencing triglyceride levels, and uncovered a pattern of association between triglycerides and coronary artery disease that suggested a causal link.

The genetic clues, uncovered by Broad Institute researcher Sekar Kathiresan, M.D., and colleagues, inspired yet another genetic investigation. Dr. Kathiresan, along with Eric Boerwinkle, Ph.D., of the University of Texas Health Science Center at Houston, and Alex Reiner, M.D., of Fred Hutchinson Cancer Research Center and the University of Washington, set out to assess the role of rare genetic variants through DNA sequencing. Their goal: to pinpoint specific genes that affect both triglyceride levels and disease risk.

By scouring the DNA of thousands of patients, the researchers discovered four rare gene mutations that not only lower the levels of triglycerides, a type of fat in the blood, but also significantly reduce a person’s risk of coronary heart disease—dropping it by 40%. The mutations all cripple the same gene, called APOC3, suggesting a powerful strategy in developing new drugs against heart disease.

These results appeared June 18 in the New England Journal of Medicine, in an article entitled “Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease.” The article describes how the researchers sequenced the protein-coding regions of 18,666 genes in each of 3,734 participants of European or African ancestry in the Exome Sequencing Project.

“We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels,” wrote the authors. “For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.”

They discovered four distinct mutations, all within the gene APOC3, that are tied to lower blood triglycerides. Remarkably, individuals carrying a single APOC3 mutation had almost 40% lower blood triglyceride levels. Normal levels are generally less than 150 milligrams per deciliter (mg/dL); with APOC3 mutations, triglyceride levels are around 85 mg/dL.

“Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations,” the authors continued. “Triglyceride levels in the carriers were 39% lower than levels in noncarriers, and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers.”

On the basis of these findings, the researchers predict that lowering triglycerides specifically through inhibition of APOC3 would have a beneficial effect by lowering disease risk. Triglyceride-lowering therapies exist, but those that are currently available have not been proven yet to stave off heart disease. This lack of effect in the studies conducted so far could be due to the therapies’ relatively modest impact on triglyceride levels compared to the sizeable effect of APOC3 mutations, which lower triglyceride levels by 80 to 90 mg/dL. The current therapies likely also act through multiple molecular targets.

Triglyceride-lowering drugs reflect an important clinical need. Doctors have recognized that even after patients are treated with drugs to lower LDL cholesterol, some still succumb to heart attacks. This so-called residual risk suggests there are other biological mechanisms at play that can raise a person's risk of heart disease.

“Although statins remain a powerful arrow in the quiver, the notion of residual risk of coronary heart disease continues to be a significant clinical problem,” said Dr. Kathiresan. “Our study really reinvigorates the idea of lowering triglycerides and specifically, by blocking APOC3, as a viable therapeutic strategy for addressing residual risk.”

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