Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

Area of Science:

• Genetics
• Cardiovascular Disease Research
• Human Genomics

Background:

• Plasma triglyceride levels are heritable and linked to coronary heart disease risk.
• Exome sequencing can identify rare mutations with significant phenotypic effects.

Purpose of the Study:

• To investigate the association between rare genetic mutations and plasma triglyceride levels.
• To evaluate the impact of these mutations on coronary heart disease risk.

Main Methods:

• Exome sequencing of 18,666 genes in 3,734 participants.
• Association tests for rare mutations (individual and aggregate) with triglyceride levels.
• Evaluation of mutation association with coronary heart disease risk in 110,970 individuals.

Main Results:

• Aggregate rare mutations in the apolipoprotein C3 (APOC3) gene were linked to lower triglyceride levels.
• Four key mutations (three loss-of-function, one missense) were identified, present in ~1 in 150 individuals.
• Carriers showed 39% lower triglyceride levels, 46% lower APOC3 levels, and a 40% reduced risk of coronary heart disease.

Conclusions:

• Disruptions in APOC3 function due to rare mutations are associated with reduced plasma triglyceride and APOC3 levels.
• Carriers of these APOC3 mutations exhibit a significantly lower risk of developing coronary heart disease.