A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease.
OBJECTIVE
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.
Hovingh
G Kees
GK
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Brownlie
Alison
A
Bisoendial
Radjesh J
RJ
Dube
Marie Pierre
MP
Levels
Johannes H M
JH
Petersen
Wilma
W
Dullaart
Robin P F
RP
Stroes
Erik S G
ES
Zwinderman
Aeilko H
AH
de Groot
Eric
E
Hayden
Michael R
MR
Kuivenhoven
Jan Albert
JA
Kastelein
John J P
JJ
D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics*; D001158:Arteries / Q000473:pathology; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000473:pathology* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D007930:Leucine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011392:Proline; D018570:Risk Assessment; D012307:Risk Factors
D016632:Apolipoprotein A-I; D011392:Proline; D007930:Leucine