Mutations in the Apolipoprotein C3 Gene Lower Triglyceride Levels and Reduce Heart Disease Risk

Mutations, which prevent the normal functioning of the APOC3 (apolipoprotein C3) gene, lower blood triglyceride levels and reduce the risk of developing coronary artery disease (CAD).

Apolipoprotein C3 is a very low density lipoprotein (VLDL) protein. APOC3 inhibits lipoprotein lipase and hepatic lipase and is thought to delay catabolism of triglyceride-rich particles.

To evaluate the linkage between triglycerides and APOC3 and the risk of developing CAD, investigators at Harvard Medical School (Cambridge, MA, USA) and colleagues at the University of Texas Health Science Center (Houston, USA) and the University of Washington (Seattle, USA) sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the [US] National Heart, Lung, and Blood Institute's Exome Sequencing Project. The investigators conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels.

After identifying four APOC3 mutations that lowered levels of circulating triglycerides, the investigators evaluated their association with the risk of coronary heart disease in 110,970 persons.

Results revealed that approximately one in 150 persons (0.67%) in the study was a heterozygous carrier of at least one of the four triglyceride-lowering mutations. Triglyceride levels in the carriers were 39% lower than levels in non-carriers, and circulating levels of APOC3 in carriers were 46% lower than levels in non-carriers. The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 non-carriers.

"The combination of our genetic results, together with recent clinical trials of drugs that raised HDL levels but failed to prevent heart disease, are turning decades of conventional wisdom on its head," said senior author Dr. Sekar Kathiresan, associate professor of medicine at Harvard Medical School. "HDL and triglycerides are both correlated with heart attack, and have an inverse relationship with one another—the lower the HDL, the higher the triglycerides. It has long been presumed that low HDL is the causal factor in heart disease, and triglycerides are along for the ride. But our genetic data indicate that the true causal factor may not be HDL after all, but triglycerides."

"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."

The study was published in the June 18, 2014, online issue of the New England Journal of Medicine (NEJM).

Related Links:
Harvard Medical School
University of Texas Health Science Center
University of Washington