Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes.

Abstract

Paraoxonase is an HDL-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. Its biallelic gene polymorphism at codon 192 (glutamine/arginine) has been associated with coronary artery disease (CAD). To further evaluate the role of this paraoxonase gene polymorphism for CAD in type 2 diabetes, we determined the paraoxonase genotype in 288 type 2 diabetic patients (170 with and 118 without angiographically documented CAD). The paraoxonase 192 Gln/Arg genotype was assessed using polymerase chain reaction followed by AlwI digestion. The frequency of the Gln allele was 0.656 in the CAD patients and 0.746 in the controls (chi2 = 5.36, P = 0.02). Compared with the Gln/Gln genotypes, the age-adjusted odds ratio for CAD was 1.78 (95% CI 1.08-2.96, P = 0.02) in subjects carrying at least one Arg allele. In the multivariate analysis, this association was even stronger after correction for the possible confounders age, sex, smoking history, and hypertension. Among current and former smokers, the odds ratio (OR) for having CAD among patients with at least one Arg allele was 3.58 (1.45-9.53, P < 0.01). The paraoxonase Arg allele was not associated with the history of myocardial infarction (OR 1.20 [0.73-1.99, NS]), but was with the extent of CAD (OR for three-vessel disease 1.92 [1.15-3.27, P = 0.01]). Our data indicate that the 192 Arg allele of the human paraoxonase gene is a risk factor for CAD but not myocardial infarction in type 2 diabetic patients, a risk factor further modified by cigarette smoking. This risk could possibly be explained by a reduced ability of the paraoxonase Arg isoform to protect lipoproteins against peroxidation.

Tobacco Smoking Modifies Association Between Gln-Arg192 Polymorphism of Human Paraoxonase Gene and Risk of Myocardial Infarction

“…An adjustment for lipid and nonlipid risk factors strengthened the association between PON1 192Arg and the risk of MI. The association that we found between PON1 192Arg and MI is consistent with the results of several studies 16,20,22,24,32,33,35,36 but not all. [17][18][19]23,25 These discrepancies could be due in part to the selection criteria of the control group, to differences in case definition, and to a lack of a population-based control group.…”

“…29,30 Perhaps this reduction in LDL protection (or in some other yet-to-be-identified activity conferred by PON1) explains the atherogenic effect of PON1 192Arg observed in the present and other studies. 16,20,22,24,32,33 HDL may play a significant role in the effect of PON1 on coronary disease. HDL cholesterol levels and paraoxonase protein levels are significantly correlated.…”

“…29,30 Carriers of the PON1 55 allele show an increased activity toward paraoxon that is independent of the PON1 192Arg allele effect. 26,31 Several studies have shown a positive association between the PON1 192Arg allele and coronary disease, 16,20,22,24,32,33 and several other studies have shown no association, [17][18][19]23,25 including 1 study of the PON1 55 polymorphism. 21 Only 2 studies with a small sample size 21,34 have evaluated the PON1 192 and the PON1 55 polymorphisms simultaneously.…”

Smoking Is Associated With Reduced Serum Paraoxonase Activity and Concentration in Patients With Coronary Artery Disease

“…Of interest in this respect is a recent study that suggests that the link we previously demonstrated between the PON B allele and the risk of vascular disease 7 may be exacerbated by smoking. 13 More important, perhaps, we demonstrate that differences in PON concentrations, on the order of those observed in the present study, can influence the ability of HDL to protect LDL from oxidation. Thus, incremental increases in HDL PON are associated with incremental decreases in the level of LDL hydroperoxides generated under oxidization conditions.…”

Glycation impairs high-density lipoprotein function

“…We found a 40 % decrease in PON activity in a group of Type II diabetic subjects with CAD compared with a group of non-diabetic subjects with CAD. Decreased PON in patients with Type II diabetes and CAD have also been found [44,45]. Polymorphisms within the PON gene that are prevalent in Type II diabetic patients with CAD have been reported [7,46].…”