Loss-of-Function Mutations in APOC3, Triglycerides and Coronary Disease

Jun 18, 2014
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Authors:
The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute.
Citation:
N Engl J Med 2014;Jun 18:[Epub ahead of print].
Summary By:
Daniel T. Eitzman, MD

Study Questions:

Are mutations associated with low triglycerides also associated with reduced cardiovascular (CV) risk?

Methods:

The protein-coding regions of 18,666 genes from 3,734 subjects were sequenced. Associations between rare mutations and triglyceride (TG) levels were identified and subsequently evaluated for association with coronary heart disease (CHD) in 110,970 subjects.

Results:

Mutations in the apolipoprotein C3 (APOC3) gene were associated with lower plasma TG levels; 1 in 150 persons was a carrier of at least 1 of 4 mutations in this gene. Levels of APOC3 and TGs were 46% (p = 8 x 10-10) and 39% (p < 1 x 10-20) lower in mutation carriers, respectively. Risk of CHD among 498 mutation carriers was 40% lower than risk among 110,472 noncarriers (p = 4 x 10-6).

Conclusions:

The authors concluded that rare mutations which disrupt APOC3 function are associated with low TGs and reduced CHD risk.

Perspective:

Although elevated TGs are associated with CHD risk, therapeutic lowering of TGs with fibrates or fish oils has not proven effective in reducing this risk, questioning the causal role of TGs in CHD. This study clearly demonstrates protection from CHD by loss-of-function mutations of APOC3, indicating that APOC3 is a viable therapeutic target for reducing CV risk. Although the reduced risk appears likely due to reduced TGs, the precise mechanism for atheroprotection will require further study.


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