The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM Study
Introduction
Paraoxonase (PON) is a high-density-lipoprotein (HDL) bound enzyme, which is coded by a gene located on chromosome 7 (7q 21–22) [1]. It catalyses the hydrolysis of organophosphates (insecticide paraoxon) and lipid peroxides. PON activity is genetically determined and two allozymic forms, A and B, have been described. The PON A-phenotype is associated with low PON activity and the PON B-phenotype with high PON activity [2]. Humbert et al. [3] have identified 2 polymorphic sites of the PON gene, affecting codons 55 (Met/Leu) and 192 (Gln/Arg). The strong association existing between the PON 192 polymorphism and PON activity suggested that this polymorphism was responsible for the human serum PON phenotypes, the PON A-phenotype being determined by the Gln allele and the PON B-phenotype, being determined by the Arg allele [4]. The PON A-phenotype has been shown to be associated with decreased levels of Apo B and triglycerides in serum [5]. Furthermore, Hegele et al. [6] in their study of a genetic isolate found that the Gln allele was associated with decreased serum levels of total cholesterol, low-density-lipoprotein (LDL) cholesterol, triglycerides and Apo B and increased serum levels of HDL cholesterol. The frequency of the PON 192 Arg allele has been shown to be increased in type 2 diabetics with CHD [7]. These observations and the fact that PON seems to protect LDL from oxidative stress by hydrolizing lipid peroxides [8], led to the hypothesis that the PON polymorphism might be a risk factor for myocardial infarction (MI).
Section snippets
Study patients
We studied the PON 192 Gln/Arg polymorphism in 642 male patients with a history of MI and in 701 age-matched controls participating in the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde). Men aged 25–64 years who had a proven MI were recruited 3–9 months after infarction in four MONICA (MONItoring trends and determinants in cardiovascular disease) centres [9]: Belfast (Northern Ireland), Lille (northern France), Strasbourg (eastern France) and Toulouse (southwestern France). Controls
Results
In the whole study population the PON genotypes were in Hardy-Weinberg equilibrium in cases with MI and controls. The genotypes and allele frequencies were similar in both groups and did not differ between populations (Table 1). The frequency of the PON 192/Arg allele in controls ranged from 0.288 in Belfast to 0.306 in Strasbourg. We also studied the distribution of PON 192 genotypes and alleles in a subsample of 405 French patients from the ECTIM Study who underwent coronary angiography. The
Discussion
The hypothesis that the PON 192 polymorphism might be a risk factor for MI was supported by the fact that PON protects LDL from oxidization [8] and by the association observed between PON phenotypes or genotypes and HDL or LDL related variables 5, 6. Hegele et al. [6] observed increased Apo B levels and decreased HDL cholesterol in subjects carrying the PON 192/Arg allele in a genetic isolate, and Saha et al. [5] found decreased Apo B and triglyceride levels in carriers of the PON A phenotype
Acknowledgements
We thank C. Souriau for the DNA extraction. This work was supported by grants from the Squibb Laboratory, the British Heart Foundation, INSERM, the ‘Institut Pasteur-Lille’, and the Groupement de Recherches et d'Etudes sur les Génomes (GREG).
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Paraoxonase 1 (Q192R) gene polymorphism, coronary heart disease and the risk of a new acute coronary event
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