Atherosclerosis 149 (2000) 435 – 442 Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases Yasushi Imai a , Hiroyuki Morita a , Hiroki Kurihara a, *, Takao Sugiyama b , Norihiro Kato c , Aya Ebihara b , Chikuma Hamada d , Yukiko Kurihara a , Takayuki Shindo a , Yoshio Oh-hashi a , Yoshio Yazaki a a Department of Cardioascular Medicine, Graduate School of Medicine, Uniersity of Tokyo, 7 -3 -1 Hongo, Bunkyo -ku, Tokyo 113 -8655, Japan b The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan c Department of Internal Medicine, Teikyo Uniersity, Tokyo, Japan d Department of Pharmacoepidemiology, Graduate School of Medicine, Uniersity of Tokyo, Tokyo, Japan Received 28 April 1999; received in revised form 20 June 1999; accepted 20 August 1999 Abstract Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 — PON2 and PON3 — were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P 0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45 – 2.79), 0.0001; ischemic stroke: 1.84 (1.34 – 2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Genetics; Paraoxonase-1; Paraoxonase-2; Coronary artery disease; Ischemic stroke; Association www.elsevier.com/locate/atherosclerosis 1. Introduction Epidemiological studies have shown that atheroscle- rosis is a multifactorial disorder, to which genetic and environmental factors contribute interactively [1,2]. Among them, the gene encoding human paraoxonase 1 (PON1 ) has been implicated in conferring genetic sus- ceptibility to coronary artery disease (CAD) [3 – 9]. Recent studies revealed that PON1, associated with high-density lipoprotein (HDL), decreases the oxidative modification of low-density lipoprotein (LDL) in vitro [10–12] and also inhibits the modification of HDL by lipid peroxide, thereby preserving HDL function [13]. The fact that PON1 possesses significant anti-athero- genic properties was confirmed using PON1-null mice: PON1-null mice were more susceptible to atherosclero- sis than their wild-type littermates [14]. Two polymorphic sites are known to exist at the PON1 locus in humans: Q/R192 (Q corresponds to A genotype and R to B genotype, respectively) and M/ L55. These two polymorphisms have significant linkage disequilibrium. Several case-control studies conducted in Caucasians and in Japanese have shown that the Q/R192 is associated with the increased risk for CAD [3–7], although others have failed to replicate this association [15 – 20]. Other studies have indicated that the Q/R192 polymorphism is associated with altered PON1 enzyme activity for paraoxon as a substrate * Corresponding author. Tel.: +81-3-58006519; fax: +81-3- 38152087. E-mail address: kuri-tky@umin.ac.jp (H. Kurihara) 0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(99)00340-8