Apolipoprotein C-Iii Deficiency

A number sign (#) is used with this entry because apolipoprotein C-III deficiency is caused by heterozygous mutation in the APOC3 gene (107720) on chromosome 11q23.

For a discussion of phenotypic features and genetic heterogeneity of hyperalphalipoproteinemia, see HALP1 (143470).

Molecular Genetics

In a family with hyperalphalipoproteinemia, von Eckardstein et al. (1991) identified a heterozygous carrier of an apolipoprotein C-III variant (107720.0002) by the presence of additional bands after isoelectric focusing (IEF) of very low density lipoprotein (VLDL). Two variant carriers exhibited plasma concentrations of HDL cholesterol and APOA1 (107680) above the 95th percentile for sex-matched controls. Their plasma concentrations of apoC-III were 30 to 40% lower than those of 2 unaffected family members and random controls.

To identify genetic factors contributing to fasting triglycerides and the postprandial triglyceride dietary response, Pollin et al. (2008) performed a single high fat feeding intervention and genomewide association study in 809 Old Order Amish individuals. They found a loss-of-function mutation in exon 2 of the APOC3 gene, R19X (107720.0003), that was tagged by a strongly associated single-nucleotide polymorphism (SNP), rs10892151, in an intron of the DSCAML1 gene (611782). Pollin et al. (2008) found that approximately 5% of Lancaster Amish individuals are heterozygous carriers of the mutation 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 suggested that lifelong deficiency of apoC-III has a cardioprotective effect. The effect of the R19X mutation on decreased fasting triglycerides and increased HDL cholesterol levels was replicated in 698 nonoverlapping Amish individuals. Pedigree and haplotype analysis were consistent with a single copy of the mutated allele having entered the population before the year 1800.

The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute (2014) sequenced the protein-coding regions of 18,666 genes in each of 3,734 participants of European or African ancestry in the Exome Sequencing Project. They then conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, the TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute (2014) subsequently evaluated their association with the risk of coronary heart disease in 110,970 individuals. An aggregate of rare mutations in the APOC3 gene was associated with lower plasma triglyceride levels. Among the 4 mutations that drove this result, 3 were loss-of-function mutations: R19X (107720.0003), IVS2+1G-A (107720.0004), and IVS3+1G-T (107720.0005). The fourth was a missense mutation (A43T; 107720.0006). Approximately 1 in 150 individuals in the study was a heterozygous carrier of at least 1 of these 4 mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (p less than 1 x 10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (p = 8 x 10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (OR = 0.60, 95% confidence interval 0.47-0.75, p = 4 x 10(-6)). The authors concluded that rare mutations that disrupt APOC3 function are associated with lower levels of plasma triglycerides and APOC3, and carriers of these mutations were found to have a reduced risk of coronary heart disease.

Jorgensen et al. (2014) used data from 75,725 participants in 2 general population studies to test whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. They then tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7,557 of these 10,797. Jorgensen et al. (2014) found that participants with nonfasting triglyceride levels of less than 1.00 mmol/L had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol/L or more. Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (p less than 0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations, with corresponding risk reductions of 41% and 36%, respectively.

Using low read-depth, whole-genome sequencing in 3,202 individuals to analyze variation influencing triglyceride levels, Timpson et al. (2014) identified a rare variant in APOC3 (rs138326449; 107720.0004). The A at this position has a minor allele frequency of approximately 0.25% in the United Kingdom and was associated with reduced plasma triglyceride levels (-1.43 SD per minor allele, p = 8.0 x 10(-8)). Timpson et al. (2014) replicated this finding in 12,831 participants from 5 additional samples of Northern and Southern European origin, finding that in carriers of the A allele, plasma triglyceride levels were lower by 1.0 SD (p = 7.32 x 10(-9)). This was consistent with an effect between 0.5 and 1.5 mmol/L, dependent upon the population. Timpson et al. (2014) showed that a single predicted splice donor variant represented by rs138326449 is responsible for association signals and is independent of known common variants.

Among the 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), Saleheen et al. (2017) identified 4 participants homozygous for the APOC3 R19X mutation (107720.0003). When compared with noncarriers, these homozygotes displayed near-absent plasma APOC3 protein (-88.9%; p = 5 x 10(-23)), lower plasma triglyceride concentrations (-59.6%; p = 7 x 10(-4)), higher HDL cholesterol (+26.9 mg/dl; p = 3 x 10(-8)), and similar levels of LDL cholesterol (p = 0.14). Saleheen et al. (2017) recontacted 1 homozygous R19X proband, his wife, and 27 of his first-degree relatives for genotyping and physiologic investigation. They found that proband's wife was also homozygous for the R19X mutation, leading to all 9 children being obligate homozygotes. In this family, they challenged all the homozygotes and noncarriers with a 50g/m(2) oral fat load followed by serial blood testing for 6 hours. The homozygotes had significantly lower postprandial triglyceride excursions (triglyceride area under the curve 468.3 mg/dl over 6 hours versus 1,267.7 mg/dl over 6 hours; p = 1 x 10(-4)). These data showed that complete lack of APOC3 markedly improved clearance of plasma triglycerides after a fatty meal, and were consistent with and extended earlier reports of diminished postprandial lipemia in APOC3 predicted loss-of-function heterozygotes.