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Papers In Press, published online ahead of print December 1, 2004
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Research Department Clinical Chemistry, UMC Utrecht, Utrecht 3584 CX
Corresponding Author: T.M.vanHimbergen{at}lab.azu.nl
Serum paraoxonase type-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, which protects low-density lipoprotein (LDL) against oxidative modification. It also inhibits the oxidation of HDL, thus preserving HDL function. Both of these properties may contribute to the protection against cardiovascular disease (CVD). We investigated the effects of PON1 levels, activity and genetic variation on HDL-cholesterol levels, circulating oxidized LDL (oxLDL), subclinical inflammation (High sensitive C-reactive protein, Hs-CRP) and on carotid intima-media thickness (IMT), a surrogate marker of CVD. PON1 genotypes (L55M, Q192R, -107C/T, -162A/G, -824G/A, and -907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 levels were measured using PON1-specific antibodies. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. OxLDL levels and Hs-CRP were determined using an immuno assay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-cholesterol levels (p values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, -107C/T, and –907G/C, respectively). There was a positive correlation between PON1 levels and activity and HDL-cholesterol (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). There was a weak correlation between diazoxonase activity, arylesterase activity and Hs-CRP (r=0.20, p=0.02 for both diazoxonase- and arylesterase activities). Neither levels of HDL-cholesterol, circulating oxLDL and Hs-CRP, nor PON1 genotypes, levels, and activity were associated with carotid IMT. Our observations support the hypothesis that both PON1 levels and activity preserve HDL-cholesterol in plasma. The relevance of this supposedly anti-atherogenic activity needs to be delineated in further studies with CVD as the clinical endpoint.
Revised on December 1, 2004
Accepted on November 20, 2004
Indications for a contribution of paraoxonase type-1 to plasma high density lipoprotein levels in patients with familial hypercholesterolemia
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