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 ... 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), dbSNP 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.