OBJECTIVES: We investigated the consequences of an apolipoprotein A-I (apoA-I) gene defect with regard to lipid metabolism, endothelial function, arterial wall thickness, and coronary artery disease (CAD) risk. BACKGROUND: Due to limited numbers of carriers of the apoA-I defects, data on the consequences of such defects have remained inconclusive. METHODS: Lipids and lipoproteins were measured in 54 apoA-I (L178P) carriers and 147 nonaffected siblings. Flow-mediated dilation (FMD) was assessed in 29 carriers and 45 noncarriers, and carotid intima-media thickness (IMT) could be determined in 33 heterozygotes and 40 controls. Moreover, CAD risk was evaluated for all apoA-I mutation carriers. RESULTS: Heterozygotes exhibited lower plasma levels of apoA-I (-50%; p < 0.0001) and high-density lipoprotein cholesterol (-63%; p < 0.0001). In addition, carriers had impaired FMD (p = 0.012) and increased carotid IMT (p < 0.001), whereas multivariate analysis revealed that heterozygotes had a striking 24-fold increase in CAD risk (p = 0.003). CONCLUSIONS: Heterozygosity for a novel apoA-I mutation underlies a detrimental lipoprotein profile that is associated with endothelial dysfunction, accelerated carotid arterial wall thickening, and severely enhanced CAD risk. Importantly, the extent of atherosclerosis in these subjects was similar to the burden of premature arterial wall abnormalities seen in patients with familial hypercholesterolemia. These data illustrate the pivotal role in humans of apoA-I in the protection against CAD.
OBJECTIVES: We investigated the consequences of an apolipoprotein A-I (apoA-I) gene defect with regard to lipid metabolism, endothelial function, arterial wall thickness, and coronary artery disease (CAD) risk. BACKGROUND: Due to limited numbers of carriers of the apoA-I defects, data on the consequences of such defects have remained inconclusive. METHODS:Lipids and lipoproteins were measured in 54 apoA-I (L178P) carriers and 147 nonaffected siblings. Flow-mediated dilation (FMD) was assessed in 29 carriers and 45 noncarriers, and carotid intima-media thickness (IMT) could be determined in 33 heterozygotes and 40 controls. Moreover, CAD risk was evaluated for all apoA-I mutation carriers. RESULTS: Heterozygotes exhibited lower plasma levels of apoA-I (-50%; p < 0.0001) and high-density lipoprotein cholesterol (-63%; p < 0.0001). In addition, carriers had impaired FMD (p = 0.012) and increased carotid IMT (p < 0.001), whereas multivariate analysis revealed that heterozygotes had a striking 24-fold increase in CAD risk (p = 0.003). CONCLUSIONS: Heterozygosity for a novel apoA-I mutation underlies a detrimental lipoprotein profile that is associated with endothelial dysfunction, accelerated carotid arterial wall thickening, and severely enhanced CAD risk. Importantly, the extent of atherosclerosis in these subjects was similar to the burden of premature arterial wall abnormalities seen in patients with familial hypercholesterolemia. These data illustrate the pivotal role in humans of apoA-I in the protection against CAD.
Authors: Adriaan G Holleboom; Lily Jakulj; Remco Franssen; Julie Decaris; Menno Vergeer; Joris Koetsveld; Jayraz Luchoomun; Alexander Glass; Marc K Hellerstein; John J P Kastelein; G Kees Hovingh; Jan Albert Kuivenhoven; Albert K Groen; Scott M Turner; Erik S G Stroes Journal: J Lipid Res Date: 2013-05-06 Impact factor: 5.922
Authors: Roshni R Singaraja; Ian Tietjen; G Kees Hovingh; Patrick L Franchini; Chris Radomski; Kenny Wong; Margaret vanHeek; Ioannis M Stylianou; Linus Lin; Liangsu Wang; Lyndon Mitnaul; Brian Hubbard; Michael Winther; Maryanne Mattice; Annick Legendre; Robin Sherrington; John J Kastelein; Karen Akinsanya; Andrew Plump; Michael R Hayden Journal: J Lipid Res Date: 2014-06-02 Impact factor: 5.922