Variation at the paraoxonase gene locus contributes to carotid arterial wall thickness in subjects with familial hypercholesterolemia.
OBJECTIVE
Paraoxonase (PON1) is a potent enzyme, physically associated with the high-density lipoprotein particle. PON1 may protect against cardiovascular disease (CVD), since it is capable of hydrolyzing oxidized LDL-cholesterol, thereby negating the detrimental effects of this lipoprotein on the arterial wall.


METHODS
In 187 patients with familial hypercholesterolemia, we studied the seven most common single nucleotide polymorphisms (SNPs) in both the coding and promoter sequences of PON1 (L55M, Q192R, T-107C, C-126G, G-162A, G-824A, and C-907G) in terms of PON1 activity and intima media thickness (IMT) of the carotid arterial wall, a validated surrogate marker for CVD.


RESULTS
In concordance with several previous studies, we observed that the L55M, T-107C, G-162A, G-824A, and C-907G SNPs conferred PON1 activity towards phenylacetate, while this was not the case for the Q192R and C-126G SNPs. Importantly, in a multivariate regression analysis, G-824A proved to be an independent predictor of carotid IMT. Additionally, the two fully discordant homozygous haplotypes, C-907/G-824/G-162/C-126/T-107/55M versus -907G/-824A/-162A/-126G/-107C/L55, differed by 22% in carotid IMT (P = 0.007).


CONCLUSIONS
Genetic variation at the PON1 locus has a strong influence on PON1 activity as well as on carotid IMT. These data indicate that PON1 is indeed involved in the pathogenesis of atherosclerosis. Whether this also translates into a role for PON1 in the occurrence of CVD events needs to be confirmed by large prospective studies in the general population.
Roest
Mark
M
Research Laboratory of the Department of Clinical Chemistry, G03-550, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. M.Roest@lab.azu.nl
Jansen
Angelique C M
AC
Barendrecht
Arjan
A
Leus
Frank R
FR
Kastelein
John J P
JJ
Voorbij
Hieronymus A M
HA
D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics*; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012044:Regression Analysis
D043303:Aryldialkylphosphatase