APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica

Abstract

Apolipoprotein C-III (apoC-III) and A-V (apoA-V) regulate triglyceride metabolism in opposite ways (1–3). In mice, the overexpression of the human APOC3 transgene (1) leads to severe hypertriglyceridemia, whereas knockout mice lacking the endogenous Apoc3 gene have hypotriglyceriemia (2). In contrast, overexpression of the human APOA5 transgene and the lack of the endogenous Apoa5 gene show opposite triglyceride effects (3). Several studies indicate that naturally occurring sequence variation in the APOC3 and APOA5 genes affects plasma triglyceride concentrations in humans (4–7). People with the G allele of the 3238C>G polymorphism (SstI site) in the 3 untranslated region (3 UTR) of APOC3 tend to have higher plasma triglyceride concentrations (4, 5), as do individuals with two minor alleles, 482C>T and 455T>C (8–10), found in the insulin response element (IRE) of the APOC3 promoter. Several minor alleles of APOA5, the 1131T>C (upstream of the proximal promoter) (3, 6, 7), c. 3A>G (in a putative Kozak sequence) (11), c.56C>G (amino acid change p.Ser19Trp in the signal peptide) (7, 11), IVS3 476G>A (3, 11), c.553G>T (amino acid change p.Gly185Cys in exon 3) (12), and c.1259T>C (located in the 3 UTR) (3, 11), are also associated with increased plasma triglyceride concentrations.