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Journal of Lipid Research, Vol. 49, 349-357, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency¹

Raul D. Santos^2,*, Ernst J. Schaefer, Bela F. Asztalos, Eliana Polisecki, Jian Wang, Robert A. Hegele, Lilton R. C. Martinez^*, Marcio H. Miname^*, Carlos E. Rochitte^*, Protasio L. Da Luz^* and Raul C. Maranhão^*

^* Lipid Clinic and Lipid Metabolism Laboratory, Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
Lipid Metabolism Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, and Tufts University School of Medicine, Boston, MA
Robarts Research Institute, London, Ontario, Canada

¹ Presented in part on November 14, 2006, at the Council on Arteriosclerosis, Thrombosis, and Vascular Biology sessions at the annual meeting of the American Heart Association, Chicago, IL.

Published, JLR Papers in Press, November 8, 2007.

² To whom correspondence should be addressed. e-mail: raul.santos{at}incor.usp.br

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon –2, Q[–2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small -3 migrating apoA-II particles, and only modestly decreased normal amounts of slow migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large -1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II -3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Supplementary key words coronary heart disease • high density lipoproteins • fat soluble vitamins • xanthomas • atherosclerosis

Abbreviations: apoA-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; TRL, triglyceride-rich lipoprotein

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