Author + information
- Received January 20, 2004
- Revision received June 2, 2004
- Accepted June 22, 2004
- Published online October 6, 2004.
- 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*,* ()
- ↵*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
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.
Dr. Kastelein is an established investigator of the Netherlands Heart Foundation (2000D039). Drs. Hovingh and Albert Kuivenhoven are supported by the Netherlands Heart Foundation (2000.115 and 1998T011, respectively). Dr. Hayden is holder of a Canada Research Chair in Human Genetics. This work was supported by grants from the Canadian Institutes of Health Researchto Dr. Hayden and from Xenon Genetics to Dr. Hayden.
- Received January 20, 2004.
- Revision received June 2, 2004.
- Accepted June 22, 2004.
- American College of Cardiology Foundation