Association between PON1 5′-regulatory region polymorphisms, PON1 activity and ischemic stroke No Soo Kim 1 , Byoung Kab Kang 1 , Min Ho Cha 1 , Se-Mi Oh, Mi Mi Ko, Ok-Sun Bang ⁎ Department of Medical Research, Korea Institute of Oriental Medicine, 461-24 Jeonmin-dong, Yuseong-gu, Daejeon, 305-811, Republic of Korea Received 31 December 2008; received in revised form 4 February 2009; accepted 5 February 2009 Available online 20 February 2009 Abstract Objectives: Paraoxonase I (PON1) was known as a risk factor for cerebrovascular diseases. This study assessed the association of single nucleotide polymorphisms (SNPs) in the PON1 5′-regulatory region with ischemic stroke and serum PON1 activity. Design and methods: Study subjects consisted of 418 healthy controls and 86 ischemic stroke patients with small vessel occlusion. SNPs were identified by DNA sequencing and a primer extension-based method. Results: Among 10 identified SNPs, only -1434GG genotype was observed with a lower frequency in patients on borderline statistical significance (OR(95% CI), 0.297(0.083–1.060), p = 0.0615). However, haplotype analysis in a dominant model revealed that ht2 was observed with a significantly lower frequency in patients (OR(95% CI), 0.390(0.153–0.991), p = 0.0477). Both C(-1434)G mutation and ht2 distribution were associated with serum PON1 activity. Conclusion: Our results suggest that haplotypes observed in the PON1 5′-regulatory region should be considered as risk factors for ischemic stroke. © 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Ischemic stroke; PON1; Polymorphism; Haplotype; Association; Risk factor Introduction Paraoxonases-1 (PON1) is implicated in atherosclerogenesis, because it can prevent atherosclerogenesis through protecting HDL and LDL from oxidative modification [1,2]. Compared with wild type littermates, PON1-null mice show higher susceptibility to atherosclerosis with high-fat diets as well as a higher degree of oxidative modification of lipoproteins [3]. Recently, it was found that PON1 can play a role as a host modulator of Pseudomonas aeruginosa quorum-sensing and interrupt the bacterial communication needed for its infectivity [4]. Therefore, it is possible that PON1 can also reduce stroke- related complications by inhibiting bacterial infection, because lipopolysaccharide endotoxin liberated by P. aeruginosa can increase the levels of TNF-α and cause damage to the vascular systems [5]. Two non-synonymous SNPs (L55M and Q192R) of PON1 were suggested to be associated with vascular diseases such as carotid disease [6] and ischemic stroke [7]. Bhattacharyya et al. [8] found that individuals with 192QQ had an increased risk of cardiovascular disease (CVD). The differences in disease susceptibility according to the Q192R genotypes may be partially explained by the fact that the 192Q form of PON1 is more effective at metabolizing oxidized lipids than the 192R form [9]. However, the association of Q192R and L55M with vascular diseases is still under debate, because other research groups failed to observe such clinical relationships [10,11]. SNPs in the PON1 5′-regulatory region can also determine the serum PON1 concentration and enzyme activity, thereby affecting the vascular disease status. For example, both C (-108)T (rs705379, C(-107)T in some reports), a potential SP1 transcription factor binding site, and G(-909)C/G(-162)A (rs854572 and rs705381, respectively) are known to affect Available online at www.sciencedirect.com Clinical Biochemistry 42 (2009) 857 – 863 ⁎ Corresponding author. Fax: +82 42 863 9464. E-mail address: osbang@kiom.re.kr (O.-S. Bang). 1 These authors contributed equally to this work. 0009-9120/$ - see front matter © 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2009.02.008