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HDL AND CORONARY ARTERY DISEASE

A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease

G. Kees Hovingh, MD^*, Alison Brownlie, PhD, Radjesh J. Bisoendial, MD^*, Marie Pierre Dube, PhD, Johannes H.M. Levels, PhD^*, Wilma Petersen, BSc^*, Robin P.F. Dullaart, MD, PhD, Erik S.G. Stroes, MD, PhD^*, Aeilko H. Zwinderman, PhD, Eric de Groot, MD, PhD^*, Michael R. Hayden, MD, PhD, ChB^,||, Jan Albert Kuivenhoven, PhD^* and John J.P. Kastelein, MD, PhD^*,*

^* Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Xenon Genetics Inc., Vancouver, British Columbia, Canada
Department of Internal Medicine, Academic Hospital, Groningen, The Netherlands
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands
^|| Center for Molecular Medicine and Therapeutics, Children and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Manuscript received January 20, 2004; revised manuscript received June 2, 2004, accepted June 22, 2004.

^* Reprint requests and correspondence: Dr. John J. P. Kastelein, Department of Vascular Medicine, F4-159.2, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands (Email: e.vandongen{at}amc.uva.nl).

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.

Abbreviations and Acronyms   apoA-I = apolipoprotein A-I   CAD = coronary artery disease   FMD = flow-mediated dilation   HDL = high-density lipoprotein   IMT = intima-media thickness   LDL = low-density lipoprotein

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