J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400052-JLR200 on December 1, 2004

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Journal of Lipid Research, Vol. 46, 445-451, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Thomas M. van Himbergen1,*,{dagger}, Mark Roest*, Jacqueline de Graaf{dagger}, Eugène H. J. M. Jansen§, Hiroaki Hattori**, John J. P. Kastelein{dagger}{dagger}, Hieronymus A. M. Voorbij*, Anton F. H. Stalenhoef{dagger} and Lambertus J. H. van Tits{dagger}

* Research Laboratory of the Department of Clinical Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands
{dagger} Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
§ Laboratory for Toxicology, Pathology, and Genetics, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
** Department of Advanced Medical Technology and Development, BML, Inc., Saitama 350-1101, Japan
{dagger}{dagger} Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

1 To whom correspondence should be addressed. e-mail: t.m.vanhimbergen{at}lab.azu.nl

HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, –107C/T, –162A/G, –824G/A, and –907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, –107C/T, and –907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03).

Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma.

Abbreviations: CCA-IMT, common carotid artery intima-media thickness; CVD, cardiovascular disease; FH, familial hypercholesterolemia; HDL-C, high density lipoprotein-cholesterol; Hs-CRP, high-sensitive C-reactive protein; LDL-C, low density lipoprotein-cholesterol; OxLDL, oxidized low density lipoprotein; PON1, paraoxonase type 1

Supplementary key words atherosclerosis • antioxidants • polymorphisms


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