A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection

Abstract

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.

Figure 1

Triglyceride levels as a function of apoC-III protein levels stratified by APOC3 R19X genotype in 20 individuals. Filled squares indicate individuals carrying the 19X allele and open squares indicate non-carriers.

Figure 2

Triglycerides levels before and during the high fat challenge by R19X APOC3 genotype. Shown are covariate-adjusted geometric means with 95% confidence intervals. Filled squares indicate individuals carrying the 19X allele and open squares indicate non-carriers.