A Null Mutation in Human APOC3 Confers a Favorable Plasma Lipid Profile and Apparent Cardioprotection

Apolipoprotein C-III ( apoC-III) inhibits triglyceride hydrolysis and has been implicated in coronary artery disease. Through a genome- wide association study, we have found that about 5% of the Lancaster Amish are heterozygous carriers of a null mutation ( R19X) in the gene encoding apoC- III ( APOC3) and, as a result, express half the amount of apoC- III present in noncarriers. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL- cholesterol and lower levels of LDL- cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, which suggests that lifelong deficiency of apoC- III has a cardioprotective effect.