Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia.
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.
van Himbergen
Thomas M
TM
Research Laboratory, Department of Clinical Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands. t.m.vanhimbergen@lab.azu.nl
Roest
Mark
M
de Graaf
Jacqueline
J
Jansen
Eugène H J M
EH
Hattori
Hiroaki
H
Kastelein
John J P
JJ
Voorbij
Hieronymus A M
HA
Stalenhoef
Anton F H
AF
van Tits
Lambertus J H
LJ
D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000201:enzymology / Q000235:genetics; D008297:Male; D010919:Placebos; D011446:Prospective Studies
D008076:Cholesterol, HDL; D010919:Placebos; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human