title: Two novel mutations in apolipoprotein C3 underlie atheroprotective lipid profiles in families.
abstract: 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.
authors.affiliation: Department of Vascular Medicine.
authors.forename: A E
authors.initials: AE
authors.lastname: Bochem
authors.forename: J C
authors.initials: JC
authors.lastname: van Capelleveen
authors.forename: G M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: A W M
authors.initials: AW
authors.lastname: Schimmel
authors.forename: M M
authors.initials: MM
authors.lastname: Motazacker
authors.forename: I
authors.initials: I
authors.lastname: Tietjen
authors.forename: R R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: J J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: E S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: G K
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D000483:Alleles; D053305:Apolipoprotein C-III / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D014280:Triglycerides / Q000097:blood / Q000235:genetics*
chemical_list: D053305:Apolipoprotein C-III; D008076:Cholesterol, HDL; D014280:Triglycerides
keywords: apolipoprotein CIII; cardiovascular disease; genetic dyslipidemia; high-density lipoprotein cholesterol; hyperalphalipoproteinemia; lipids; lipoproteins; mutations; triglycerides