Abstract 15586: Null Mutations in APOC3 Are Not Uncommon in the General Population, Confer a Favorable Lipid Profile, and Apparent Cardioprotection
Objectives: Apolipoprotein C-III (apoC-III) inhibits triglyceride hydrolysis and has been implicated in coronary artery disease. The objective of the present study was to determine the frequency of genetic variants in APOC3 in the general population, and the effect on lipid and lipoprotein levels and on risk of ischemic heart disease (IHD).
Methods and Results: A null mutation in APOC3, R19X, has previously been identified in the Lancaster Amish in whom it associated with a reduction in subclinical atherosclerosis as measured by coronary artery calcification. By resequencing APOC3 in the entire Copenhagen City Heart Study (n=10.396), we found that about 0.4% of the general population are heterozygous carriers of null mutations. In the CCHS, heterozygotes for null mutations in APOC3 compared with noncarriers had 45% lower plasma levels of nonfasting triglycerides and remnant cholesterol (P<0.001), 25% higher levels of HDL cholesterol (P<0.001), and no change in LDL cholesterol. The observed reduction in plasma triglycerides in heterozygotes predicted an approximate 40% reduction in risk of IHD compared with noncarriers which was comparable to the risk reduction in IHD actually observed in the CCHS (P<0.05).
Conclusion: Naturally occurring null mutations in APOC3 are not uncommon in the general population, and confer a favorable lipid profile and apparent protection against IHD. It is therefore likely, that therapies aimed at specifically downregulating apoC-III expression may reduce morbidity and mortality associated with IHD.
- © 2011 by American Heart Association, Inc.