Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Do loss-of-function mutations in the gene encoding apolipoprotein C3 (APOC3) lead to reduced triglyceride (TG) levels and protection from cardiovascular disease (CVD)?
The relationships between low levels of nonfasting TGs, APOC3 mutations, and ischemic heart disease were analyzed in 75,725 subjects from two general population studies. Ischemic vascular disease developed in 10,797 subjects during follow-up, which included 7,557 subjects with ischemic heart disease.
Subjects with nonfasting TG levels <90 mg/dl had a lower incidence of CVD than those with TG levels >350 mg/dl (hazard ratio, 0.43 for ischemic vascular disease and 0.40 for ischemic heart disease). Heterozygous loss-of-function APOC3 mutations were associated with 44% reduction in nonfasting TGs (p < 0.001). The incidences of ischemic vascular disease and ischemic heart disease were reduced by 41% and 36%, respectively, in subjects with APOC3 mutations.
The authors concluded that APOC3 loss-of-function mutations are associated with low TG levels and reduced risk for ischemic vascular disease.
The role of TGs in vascular disease is controversial. This study demonstrates that lifelong low levels of TGs due to APOC3 mutations lead to markedly reduced risk for vascular disease. APOC3 is therefore a potentially valuable therapeutic target for the primary and secondary prevention of ischemic vascular events.
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