The Gln–Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan

Abstract

Paraoxonase (PON1) is a high density lipoprotein-associated enzyme capable of hydrolyzing lipid peroxides, and thus, might protect lipoproteins from oxidation. A common polymorphism due to an amino acid substitution (Gln–Arg) at codon 191 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1-191 polymorphism is an independent risk factor for coronary atherosclerosis in patients with or without diabetes mellitus. The association of PON1-191 polymorphism genotypes and coronary artery disease (CAD) among Chinese subjects in Taiwan was examined. The genotype of 218 angiographically documented CAD patients and the same number of age- and sex-matched control subjects was determined. Genotypes AA, AB and BB were present in 25 (11%), 102 (47%) and 91 (42%) of control subjects, respectively, and in 30 (14%), 96 (44%) and 92 (42%) of CAD patients, respectively (χ²=0.57, P=0.75 between groups). The frequency of the A allele was 0.36 for the control group and 0.35 for CAD patients (P=0.94). No significant differences in the PON1-191 genotype frequencies could be found between groups when multivariate logistic regression analysis was performed, or different subgroups of age, sex or risk factors were analyzed. Among control subjects, there was also no significant difference between genotypes of the PON1-191 polymorphism and various clinical and lipid variables. In conclusion, our data suggest that there is no association between the Gln–Arg 191 polymorphism of the human PON1 gene and CAD among Chinese subjects in Taiwan.

Introduction

Atherosclerotic coronary artery disease (CAD) is now a major health problem in many industrialized countries, including Taiwan, and contributes significantly to morbidity and mortality. Numerous epidemiological studies have revealed that hypercholesterolemia, hypertension and smoking are major risk factors for CAD. There is also increasing evidence that genetic factors may play an important and independent role in predisposition to CAD and its thrombotic complication [1], [2]. Recent reports of molecular genetic analyses using allelic association studies have suggested that genetic polymorphisms of the genes involved in lipid metabolism, coagulative and fibrinolytic pathways, and the renin–angiotensin system may be associated with coronary atherosclerosis or myocardial infarction (MI) [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. These findings are, however, still controversial.

Paraoxonase (PON1) has been implicated in the pathogenesis of atherosclerosis. PON1 is an aryldialkylphosphatase that hydrolyzes paraoxon, an active toxic metabolite of parathion, thus providing protection against organophosphate poisoning. Its physiological substrate is unknown. PON1 is exclusively bound to high density lipoprotein (HDL) and has been shown to prevent low density lipoprotein (LDL) oxidation in vitro [13], [14]. This may partly explain how HDL protects LDL from oxidation. Oxidation of LDL appears to play an important role in the development and progression of atherosclerotic lesions [15], [16]. While the serum level of PON1 in a given individual is relatively stable over time, there is wide variation in the level of serum PON1 activity in humans. The PON1 enzymatic activity polymorphism is substrate-dependent and varies among populations of different ethnic background [17], [18], [19]. The genetic basis of the inter-individual variability of PON1 activity has recently been attributed to the presence of a glutamine (Gln)/arginine (Arg) polymorphism at amino acid position 191 and a leucine/methionine polymorphism at amino acid position 54 of the PON1 protein [20], [21], [22]. Subjects homozygous for Arg at position 191 (BB genotype) show a significantly higher serum PON1 activity of certain substrates than those homozygous for Gln (AA genotype) [20]. Recently, decreased PON1 activity has been documented in patients with MI [23]. The BB genotype has been found to be associated with an increased risk of CAD in several recent studies [24], [25], [26], but not in others [27], [28], [29]. To determine whether an association between PON1-191 polymorphism and CAD exists in a Chinese population, we analyzed the PON1-191 genotype of 436 Chinese subjects living in Taiwan.