Two novel mutations in apolipoprotein C3 underlie atheroprotective lipid profiles in families

Apolipoprotein C3 (APOC3) mutations carriers typically display high plasma high-density lipoprotein cholesterol (HDL-C) and low triglycerides (TGs). We set out to investigate the prevalence and clinical consequences of APOC3 mutations in individuals with hyperalphalipoproteinemia. Two novel mutations (c.-13-2A>G and c.55+1G>A) and one known mutation (c.127G>A;p.Ala43Thr) were found. Lipid profiles and apoCIII isoform distributions were measured. c.55+1G>A mutation carriers displayed higher HDL-C percentiles (35.6 +/- 35.8 vs 99.0 +/- 0, p = 0.002) and lower TGs (0.51 (0.37-0.61) vs 1.42 (1.12-1.81) mmol/l, p = 0.007) and apoCIII levels (4.24 +/- 1.57 vs 7.33 +/- 3.61 mg/dl, p = 0.18). c.-13-2A>G mutation carriers did not display significantly different HDL-C levels (84.0 +/- 30.0 vs 63.7 +/- 45.7, p = 0.50), a trend towards lower TGs [0.71 (0.54 to 0.78) vs 0.85 (0.85 to -) mmol/l, p = 0.06] and significantly lower apoCIII levels (3.09 +/- 1.08 vs 11.45 +/- 1.06 mg/dl, p = 0.003). p.Ala43Thr mutation carriers displayed a trend towards higher HDL-C percentiles (91.2 +/- 31.8 vs 41.0 +/- 29.7 mmol/l, p = 0.06) and significantly lower TGs [0.58 (0.36-0.63) vs 0.95 (0.71-1.20) mmol/l, p = 0.02] and apoCIII levels (4.92 +/- 2.33 vs 6.60 +/- 1.60, p = 0.25). Heterozygosity for APOC3 mutations results in high HDL-C and low TGs and apoCIII levels. This favourable lipid profile in patients with genetically low apoCIII levels holds promise for current studies investigating the potential of apoCIII inhibition as a novel therapeutic in cardiovascular disease prevention.