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Open Access Research article

Association between paraoxonase gene and stroke in the Han Chinese population

Guojun Zhang1, Wenjin Li2, Zhiqiang Li2, Hong Lv1, Yonghong Ren34, Ruimin Ma1, Xiaohong Li34, Xixiong Kang1, Yongyong Shi2* and Yimin Sun34*

Author Affiliations

1 Laboratory Diagnosis Center, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, 100050, China

2 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China

3 CapitalBio Corporation, 18 Life Science Parkway, Changping District, Beijing, 102206, China

4 National Engineering Research Center for Beijing Biochip Technology, 18 Life Science Parkway, Changping District, Beijing, 102206, China

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BMC Medical Genetics 2013, 14:16  doi:10.1186/1471-2350-14-16

The electronic version of this article is the complete one and can be found online at:

Received:3 April 2012
Accepted:22 January 2013
Published:28 January 2013

© 2013 Zhang et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



The human paraoxonase (PON) gene family has three isoforms: PON1, PON2 and PON3. These genes are implicated as potential risk factors of cerebrovascular disease and can prevent oxidative modification of low-density lipoproteins and atherosclerosis. This study evaluated the association between the genetic variants of all three PON genes and the risks of total stroke, ischemic stroke and hemorrhagic stroke in the Han Chinese population.


A total of 1016 subjects were recruited, including 508 healthy controls and 498 patients (328 with ischemic stroke and 170 with hemorrhagic stroke). A total of 11 single nucleotide polymorphisms (SNPs) covering the PON genes were genotyped for statistical analysis. Two of the 11 SNPs (rs662 and rs854560) were contextualized in a meta-analysis of ischemic stroke.


The presence of rs705381 (−162) in the promoter region of PON1 was significantly associated with total stroke (Padjusted = 0.0007, OR = 0.57 [95% CI = 0.41-0.79]) and ischemic stroke (Padjusted = 0.0017, OR = 0.54 [95% CI = 0.37-0.79]) when analyzed using a dominant model, but was not associated with hemorrhagic stroke. There was also a nominal association between rs854571 (−824) and total stroke. Meta-analysis demonstrated a significant nominal association between rs662 and ischemic stroke, but there was no evidence of an association between rs662 and ischemic stroke risk in a single site association study.


These findings indicate that polymorphisms of PON1 gene may be a risk factor of stroke.

Polymorphisms; Paraoxanase gene; Hemorrhagic stroke; Ischemic stroke; Association


Stroke is recognized as one of the leading causes of death and severe neurological disability worldwide. Ischemic and hemorrhagic stroke are the two primary subtypes [1]. Data from family-based studies [2], twin studies [3,4], and animal experiments [5,6] indicate that genetic factors play a major role in stroke. A small isolated group of strokes have previously been ascribed to single-gene disorders [7].

Intermediate phenotypes of stroke are seen clinically. Atherosclerosis, as an intermediate phenotype of stroke, has been extensively investigated as a major underlying cause of cardio- and cerebrovascular disease [8-10]. There is also a strong inverse association between high-density lipoprotein (HDL) levels and the development of atherosclerosis, and similar results have been found between low-density lipoprotein (LDL) peroxidation and the development of atherosclerosis [11,12].

The paraoxonase (PON) gene family comprises three isoforms, PON1, PON2 and PON3, located in 7q21.3-22.1 [13]. The 60 to 80% structural similarity among these three members accounts for their functional similarity [13,14]. All three isoforms have been implicated as candidate genes for atherosclerosis and cardiovascular diseases due to their ability to attenuate lipid peroxidation, and due to their antioxidant and antiatherogenic effects [15-17]. Low levels of PON activity are thought to increase the risk of atherosclerosis [18], and thereby contribute to a predisposition towards stroke, coronary artery disease (CAD) and vascular disorders in diabetes [19-21]. Other studies have demonstrated a positive association between single nucleotide polymorphisms (SNPs) in PON genes and stroke susceptibility [22-25], although conflicting results have been seen in different ethnic groups [26-28]. However, there are limited number of prospective studies validating the association between PON genes and the risk of stroke in the Han Chinese population [26,28-30].

A negative association has previously been demonstrated between SNPs in the coding region of PON1 and PON2, and the development of stroke. In this study we wanted to evaluate the levels of ischemic and hemorrhagic risk conferred by SNPs in the whole PON family in a large Chinese population. With this aim in mind, we conducted a case–control study in the Han Chinese population to evaluate the possible association of PON family genes with total stroke and its subtypes.



The study sample included 508 healthy controls and 498 patients, including 328 with ischemic stroke and 170 with hemorrhagic stroke who presented consecutively to the Department of Neurology, Beijing Tiantan Hospital, between December 2010 and March 2011. The subjects were unrelated to one another and were recruited from the Han Chinese population.

Hemorrhagic stroke included hypertensive cerebral hemorrhage and subarachnoid hemorrhage. Patients with hemorrhage due to trauma, tumor, vascular malformation and coagulopathy were excluded. Ischemic stroke was defined as a sudden onset of focal or global neurologic deficit with signs and symptoms persisting for more than 24 h. Patients with a history or occurrence of transient ischemic attack, cerebral embolism, cerebral trauma, cerebrovascular malformations, coagulation disorders, autoimmune diseases, tumors, peripheral vascular disease, or chronic infection diseases were excluded from the study.

All diagnoses were confirmed by brain computed tomography and/or magnetic resonance imaging. The brain images were independently assessed by a technologist and a physician.

Control subjects were recruited from the health examination department of the Beijing Tiantan Hospital. These subjects had no clinical or radiological evidence of stroke and other neurological diseases. They were also free from autoimmune disease, liver disease, nephrosis, and hematological disorders

Sex, age, total plasma cholesterol (TC), triglycerides (TG), HDL, and LDL cholesterol were documented on entry into the study. Potential vascular risk factors were evaluated, including hypertension, diabetes mellitus, atrial fibrillation, and ischemic heart disease. Hypertension was defined according to WHO/ISH criteria [31] as systolic blood pressure ≥140 mmHg and/or diastolic pressure ≥ 90 mmHg with concomitant use of antihypertensive medications Diabetes mellitus was defined as fasting plasma glucose ≥7.0 mmol/L or current treatment with anti-diabetic drugs.

The experimental protocol was approved by the Ethics Committee of the Beijing Tiantan Hospital. Written informed consent was obtained from all participants prior to entering the study.


Eleven single nucleotide polymorphisms (SNPs) were genotyped. These included: rs662 (Gln192Arg), rs13306698 (Arg160Gly), rs854560 (Leu55Met) in coding region of PON1; rs705379 (−107/-108), rs705381 (−160/-162), rs854571 (−824/-832), rs854572 (−907/-909) in the promoter of PON1; rs12026 (Ala148Gly) and rs7493 (Ser311Cys) of PON2, together with rs2074353 (located in intron) and rs1053275 (Ala99Ala) for PON3.

The SNPs were genotyped using the Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) according to the iPLEX Gold Application Guide available at ( webcite). The genotyping analysis was undertaken according to the manufacturer’s protocol, using recommended reagents in the iPLEX Gold SNP genotyping kit. Briefly, specific assays were designed using the Mass ARRAY Assay Design software package (v3.1). The process involved a locus-specific PCR reaction based on a locus-specific primer extension reaction. Residual nucleotides were dephosphorylated with SAP enzymes before undertaking the iPLEX GOLD primer extension reactions.

Following the single-base extension reactions the products were desalinated with Spectro CLEAN resin (Sequenom). A 10 nL aliquot of the desalinated product was spotted onto a 384-format Spectro CHIP with the Mass ARRAY Nanodispenser. Mass determination was carried out with the MALDI-TOF mass spectrometer and Mass ARRAY Type 4.0 software was used for data acquisition.

SNP genotypes were named using cluster analysis with a default parameter setting. Genotypes were further reviewed manually to correct classification errors caused by clustering artifacts.

Statistical analysis

Statistical analysis was undertaken using PLINK software ( [32]. Hardy-Weinberg equilibrium tests (HWE) were performed for each SNP, and association tests were undertaken using additive, dominant, or recessive genetic models.

Logistic regression was used for risk stratification with or without covariate adjustments determined by significant differences between total stroke patients and controls (i.e. age, HDL, and hypertension). The model with the highest likelihood was considered to provide the best-fit genetic model for each SNP. Haplotype-based association analysis was performed using logistic regression with or without adjustment for covariates. A single site association test between rs662 and rs854560 and ischemic stroke was conducted using an allele-based model. Bonferroni correction was undertaken for the 10 SNPs that were adopted into the single site association analysis.

Linkage disequilibrium analysis and haplotype selection were performed using Haploview software with parameter settings for pairwise tagging with D’ >0.95 [33]. The Omnibus ANOVA test was conducted using R software [34].

Inverse variance meta-analysis (RevMan 4.0 software) was used to contextualize our studies with two meta-analyses, using the data from PMID: 20856122 [35] and PMID: 18511872 [30], which also studied the association between rs662 and rs854560 loci and ischemic stroke.

Values of P <0.005 were considered to represent the threshold for statistical significance.


Clinical characteristics of total stroke patients and controls

Table 1 shows demographic characteristics and clinical vascular variables in the control and total stroke patients. There were no significant differences in levels of TC, TG and LDL between the controls and total stroke cases. However, HDL levels were significantly lower in stroke cases than in controls and mean age and incidence of hypertension were significantly higher.

Table 1. Comparison of clinical variables between total strokes and control subjects

Linkage disequilibrium

A total of eleven gene polymorphisms were genotyped in the cases and controls. For PON1 these included three coding-region polymorphisms (rs662/Q192R, rs13306698/Arg160Gly, and rs854560/Leu55Met) and four regulatory-region polymorphisms (rs705379/-107/-108, rs705381/-160/-162, rs854571/-824/-832, and rs854572/-907/-909). There were also two coding-region polymorphisms of PON2 (rs12026/Ala148Gly, and rs7493/Ser311Cys), and two coding-region polymorphisms of PON3 (rs2074353 located in intron and rs1053275/Ala99Ala). The total rate of successful genotyping was 98.6%. All genotype distributions within the studied polymorphisms were in Hardy-Weinberg equilibrium (P >0.05), in both cases and controls, except for rs705379 (−107/-108) (P <0.001), which was located in the promoter of PON1.

The results of linkage disequilibrium evaluation analyses are shown in Figure 1A. In this analysis, SNPs with a pairwise r2 >0.9 were considered to be in the same block. Based on this approach, four haplotype blocks (Block1: rs854560-rs13306698-rs662; Block2: rs854572-rs854571-rs705381; Block3: rs1053275-rs2074353; Block4: rs12026-rs7493) were identified (Figure 1B).

thumbnailFigure 1. Linkage disequilibrium analysis of the ten SNPs investigated in healthy controls (a). Four blocks were identified using Haploview software: Block1 (rs854560-rs13306698-rs662); Block2 (rs854572-rs854571-rs705381); Block3 (rs1053275-rs2074353); Block4 (rs12026-rs7493) (b).

Single site association

The association between the ten SNPs included in the four blocks and total stroke occurrence was analyzed using additive, dominant, genotype, and recessive models. As shown in Table 2, two polymorphisms, rs705381 and rs854571 were significantly associated with total stoke using additive and dominant models. The allele A of rs705381 and the allele T of rs854571 were both less frequent in patients with total stroke than in controls. The association remained significant after logistic regression analysis adjusting for age, HDL and hypertension using the additive model (rs705381, Padjusted = 0.0058, OR = 0.67 [95% CI = 0.50-0.89]; and rs854571, Padjusted = 0.0330, OR = 0.80 [95% CI = 0.65-0.98]). However, both P-values failed to reach significance after the Bonferroni adjustment for multiple comparisons. Analysis using the dominant model, showed that the differences in rs705381 remained significant after Bonferroni correction (Padjusted = 0.0007, OR = 0.57 [95% CI = 0.41-0.79]), but the differences in rs854571 did not. There was no significant association between any of the SNPs of PON genes and total strokes when analyzed using the recessive model.

Table 2. Association between SNPs and total stroke using the additive, dominant, genotype, and the recessive models

As shown in Table 3, rs705381 was significantly associated with ischemic stroke after adjustment of confounders in both additive and dominant models (Padjusted = 0.0017, OR = 0.54 [95% CI = 0.37-0.79]). However, no significant association with ischemic stroke was found using the recessive model.

Table 3. Association between SNPs with ischemic stroke using the additive, dominant, genotype, and the recessive models

Rs854571 was associated with hemorrhagic stroke, with marginal significance (Punadjusted = 0.0500, OR = 0.76 [95% CI = 0.57-1.00]) using the additive model, and rs705381 showed a significant association in both additive (Padjusted = 0.0290, OR = 0.62 [95% CI = 0.40-0.95]) and dominant models (Padjusted = 0.0165, OR = 0.57 [95% CI = 0.36-0.90]) (Table 4). However, neither of the two SNPs was significantly associated with hemorrhagic stroke after the Bonferroni correction. Thus, there was no significant finding for hemorrhagic stroke with any of the three models.

Table 4. Association between SNPs and hemorrhagic stroke using the additive, dominant, genotype, and the recessive models

Haplotype analysis

Haplotype analysis conducted in the four blocks, with or without adjustment for age, HDL and hypertension as covariates is shown in Table 5. Block 2 consisting of rs854572, rs854571 and rs705381 was associated with total stroke (P = 0.0129 Omnibus test), and included one protective haplotype C-T-C (OR = 0.64; Punadjusted = 0.0013,) and one nominal risk haplotype C-C-C (OR = 1.24; Punadjusted = 0.0442,). The association for haplotype C-T-C remained significant after adjustment for age, HDL and hypertension as covariates (OR = 0.65; P = 0.0037). No other significant haplotype associations were found.

Table 5. Haplotypes of the four blocks between total strokes and control subjects


Two meta-analyses, PMID: 20856122 [35] and PMID: 18511872 [30], which studied the association between rs662 and rs854560 loci and ischemic stroke were contextualized with our study using the random effects model. Forests plot for rs662 from 25 studies including our own are shown in Figure 2. There was a nominal significant association between rs662 and ischemic stroke (P = 0.0100, OR = 1.08 [95% CI = 1.02-1.15]) yielding 1.08 per G allele copy, with no statistical evidence for statistical heterogeneity (P = 0.0400, I2 = 36%) between studies.

thumbnailFigure 2. Meta-analysis of studies investigating the association of PON1 rs662 with ischemic stroke using a random effects model. The point estimate of the OR (square proportional to the weight of each study) and 95% CI for the OR (extending lines) for each study. The summary OR and 95% CIs by random effects calculations are depicted as a diamond. Values higher than 1 indicate that the G allele is associated with increased risk of ischemic stroke.

There was no evidence of an association between rs854560 and ischemic stroke risk (P = 0.3700, OR = 0.97 [95% CI = 0.91-1.04]) and no evidence of heterogeneity (P = 0.2700, I2 = 16%) between studies (Figure 3).

thumbnailFigure 3. Meta-analysis of studies investigating the association of PON1 rs854560 with ischemic stroke using a random effects model. Values higher than 1 indicate that the A allele is associated with increased risk of ischemic stroke risk. The layout is the same as that in Figure 2.


The present study investigated the association of 11 polymorphisms in 3 PON genes with the risk of stroke. Using a dominant model, we demonstrated that rs705381 (−162) was significantly associated with total stroke and ischemic stroke but not with hemorrhagic stroke. There was also a nominal association between rs854571 (−824) and stroke with the allele T as a protective factor.

Both rs705381 and rs854571 polymorphisms located in the promoter region of PON1 were associated with stroke, which was consistent with previous findings [19,36-39]. The protective effect of -162 T polymorphism on total stroke and ischemic stroke was also consistent with previous observations [40] which suggested that NF-1, a ubiquitous nuclear factor and a transcriptional activator, has a binding site on PON1 if allele A appears at −162. Other studies have shown that -162 T polymorphism results in higher expression levels of PON1[40,41] There is also evidence to suggest a correlation between AA (−162) and high PON activities in Caucasians [42].

Our results support the hypothesis that the protective effect of -162 T polymorphism might be attributable to high PON activity [42]. We also found weak evidence to suggest that -824 T was associated with a reduced propensity to suffer stroke. However, the evidence was no longer apparent after Bonferroni correction for multiple comparisons. It has been previously reported that -824 T (824A in their finding) was associated with low serum PON levels [43]. Negative associations between −162 and −824 have been reported in studies in American populations [23,40]. These findings highlight the potential influence of ethnic differences in terms of the founder effect and identical-by-descent principles [44,45].

Patients with coronary heart disease (CHD) have been shown to have a higher frequency of -162 T allele than the controls, suggesting allele A may be associated with risk of CHD in the Han Chinese population [46]. However, in our study, we found a protective effect of the -162 T polymorphism on stroke.

Haplotype analysis further confirmed our positive results and identified a positive association between the protective haplotype C-T-C and the risk haplotype C-C-C of rs854572-rs854571-rs705381 (Block 2) with total stroke. No significant associations were observed for stroke susceptibility with the two coding region polymorphisms in PON2, which was consistent with previous findings in the Han Chinese population and in North Americans [24,29], although a positive association of Ser311Cys was found in a Polish population [22].

The absence of any positive correlations between stroke risk and the two PON3 polymorphisms in our study was also consistent with reported findings in Caucasian and North American patients [24,27].

Our study was conducted in a relatively large Chinese sample pool and included careful assessment of two stroke subtypes. We also selected common variants in all three members of the PON gene family. However, functional detection of PON activities was not undertaken in the present study and investigation of the association between SNPs and large or small vessel strokes was not possible as a complete classification of the subtype of ischemic stroke subjects was not available in our study. In our study, results from both adjusted and unadjusted analyses were in line with each other. However, in other settings, authorities have discouraged the use of data adjustments for the determination of the total genetic effect [47]. It, therefore, remains uncertain as to whether adjusted or unadjusted data should be used to interpret our results in clinical context.


The study identified rs705381 (−162) as being significantly associated with total stroke and ischemic stroke, and demonstrated a weak association for rs854571 (−824) in the Han Chinese population. These findings support the involvement of PON polymorphisms in the development of stroke. Further studies with larger sample sizes are required to validate these findings and to elucidate the underlying biological mechanisms.

Competing interests

The authors have no competing interests.

Authors’ contributions

YS and YS designed the study, coordinated sample recruitment and revised the final manuscript. GZ participated in study design and collected the samples. WL drafted the manuscript and carried out the statistical analysis. ZL helped with the statistical analysis and draft manuscript preparation. HL, RM and XK helped with the sample collection. YR and XL performed the SNP genotyping. All authors read and approved the final manuscript.


The project was supported by National Key Technology R&D Program in the 11th Five year Plan of China (2008BAI52B03), the Natural Science Foundation of China (81130022, 81272302, 31000553), the National 863 project (2012AA02A515), the Foundation for the Author of National Excellent Doctoral Dissertation of China (201026), and Shanghai Science and Technology Development Funds (12QA1401900).


  1. Adams H, Bendixen B, Kappelle L, Biller J, Love B, Gordon D, Marsh E: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.

    Stroke 1993, 24(1):35-41. OpenURL

  2. Liao DP, Myers R, Hunt S, Shahar E, Paton C, Burke G, Province M, Heiss G: Familial history of stroke and stroke risk - The family heart study.

    Stroke 1997, 28(10):1908-1912. OpenURL

  3. de Lange M, Snieder H, Ariens RAS, Spector TD, Grant PJ: The genetics of haemostasis: a twin study.

    Lancet 2001, 357(9250):101-105. OpenURL

  4. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K: Genetic liability in stroke - a long-term follow-up study of Danish twins.

    Stroke 2002, 33(3):769-774. OpenURL

  5. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K: Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.

    Nat Genet 1996, 13(4):429-434. OpenURL

  6. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, Macrae IM, Dominiczak AF: Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.

    Nat Genet 1997, 16(4):364-367. OpenURL

  7. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, et al.: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

    Nature 1996, 383(6602):707-710. OpenURL

  8. Petersen NH, Schmied AB, Zeller JA, Plendl H, Deuschl G, Zunker P: Lp(a) lipoprotein and plasminogen activity in patients with different etiology of ischemic stroke.

    Cerebrovasc Dis 2007, 23(2–3):188-193. OpenURL

  9. Lernfelt B, Forsberg M, Blomstrand C, Mellstrom D, Volkmann R: Cerebral atherosclerosis as predictor of stroke and mortality in representative elderly population.

    Stroke 2002, 33(1):224-229. OpenURL

  10. Nagai Y, Kitagawa K, Sakaguchi M, Shimizu Y, Hashimoto H, Yamagami H, Narita M, Ohtsuki T, Hori M, Matsumoto M: Significance of earlier carotid atherosclerosis for stroke subtypes.

    Stroke 2001, 32(8):1780-1785. OpenURL

  11. Gordon DJ, Rifkind BM: High-density lipoprotein — the clinical implications of recent studies.

    N Eng J Med 1989, 321(19):1311-1316. OpenURL

  12. Kozarsky KF, Donahee MH, Glick JM, Krieger M, Rader DJ: Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse.

    Arterioscler Thromb Vasc Biol 2000, 20(3):721-727. OpenURL

  13. Primo-Parmo SL, Sorenson RC, Teiber J, Du BNL: The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family.

    Genomics 1996, 33(3):498-507. OpenURL

  14. Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, Shih DM, Lusis AJ, Navab M, Fogelman AM: Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids.

    Arterioscler Thromb Vasc Biol 2001, 21(4):542-547. OpenURL

  15. Mackness MI, Arrol S, Durrington PN: Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein.

    FEBS Lett 1991, 286(1–2):152-154. OpenURL

  16. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN: Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions - a possible peroxidative role for paraoxonase.

    J Clin Invest 1998, 101(8):1581-1590. OpenURL

  17. Tward A, Xia Y-R, Wang X-P, Shi Y-S, Park C, Castellani LW, Lusis AJ, Shih DM: Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice.

    Circulation 2002, 106(4):484-490. OpenURL

  18. Mackness MI, Arrol S, Abbott CA, Durrington PN: Is paraoxonase related to atherosclerosis.

    Chem Biol Interact 1993, 87(1–3):161-171. OpenURL

  19. Kim NS, Kang K, Cha MH, Kang BJ, Moon J, Kang BK, Yu BC, Kim YS, Choi SM, Bang OS: Decreased paraoxonase-1 activity is a risk factor for ischemic stroke in Koreans.

    Biochem Biophys Res Commun 2007, 364(1):157-162. OpenURL

  20. Michalak S, Kazmierski R, Hellmann A, Wysocka E, Kocialkowska-Adamczewska D, Wencel-Warot A, Nowinski WL: Serum paraoxonase/arylesterase activity affects outcome in ischemic stroke patients.

    Cerebrovasc Dis 2011, 32(2):124-132. OpenURL

  21. Martinelli N, Micaglio R, Consoli L, Guarini P, Grison E, Pizzolo F, Friso S, Trabetti E, Pignatti PF, Corrocher R, et al.: Low levels of serum paraoxonase activities are characteristic of metabolic syndrome and may influence the metabolic-syndrome-related risk of coronary artery disease.

    Exp Diabetes Res 2012, 2012:231502. OpenURL

  22. Slowik A, Wloch D, Szermer P, Wolkow P, Malecki M, Pera J, Turaj W, Dziedzic T, Klimkowicz-Mrowiec A, Kopec G, et al.: Paraoxonase 2 gene C311S polymorphism is associated with a risk of large vessel disease stroke in a Polish population.

    Cerebrovasc Dis 2007, 23(5–6):395-400. OpenURL

  23. Voetsch B, Benke KS, Panhuysen CI, Damasceno BP, Loscalzo J: The combined effect of paraoxonase promoter and coding region polymorphisms on the risk of arterial ischemic stroke among young adults.

    Arch Neurol 2004, 61(3):351-356. OpenURL

  24. Ranade K, Kirchgessner TG, Iakoubova OA, Devlin JJ, DelMonte T, Vishnupad P, Hui L, Tsuchihashi Z, Sacks FM, Sabatine MS, et al.: Evaluation of the paraoxonases as candidate genes for stroke - Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.

    Stroke 2005, 36(11):2346-2350. OpenURL

  25. Voetsch B, Benke KS, Damasceno BP, Siqueira LH, Loscalzo J: Paraoxonase 192 Gln - > Arg polymorphism - an independent risk factor for nonfatal arterial ischemic stroke among young adults.

    Stroke 2002, 33(6):1459-1464. OpenURL

  26. Xiao ZJ, Chen J, Sun Y, Zheng ZJ: Lack of association between the Paraoxonase 1 Q/R192 single nucleotide polymorphism and stroke in a Chinese cohort.

    Acta Neurol Belg 2009, 109(3):205-209. OpenURL

  27. Pasdar A, Ross-Adams H, Cumming A, Cheung J, Whalley L, St Clair D, MacLeod MJ: Paraoxonase gene polymorphisms and haplotype analysis in a stroke population.

    BMC Med Genet 2006, 7:28. OpenURL

  28. Huang Q, Liu Y-h, Yang Q-d, Xiao B, Ge L, Zhang N, Xia J, Zhang L, Liu Z-j: Human serum paraoxonase gene polymorphisms, Q192R and L55M, are not associated with the risk of cerebral infarction in Chinese Han population.

    Neurolog Res 2006, 28(5):549-554. OpenURL

  29. Xu HW, Yuan N, Zhao Z, Zhang L, Xia J, Zeng KM, Xiao B, Yang XS, Tang BS: Study of the relationship between gene polymorphisms of paraoxonase 2 and stroke in a chinese population.

    Cerebrovasc Dis 2008, 25(1–2):87-94. OpenURL

  30. Xu XW, Li JJ, Sheng WL, Liu L: Meta-analysis of genetic studies from journals published in China of ischemic stroke in the Han Chinese population.

    Cerebrovasc Dis 2008, 26(1):48-62. OpenURL

  31. Afridi I, Canny J, Yao CH, Christensen B, Cooper RS, Kadiri S, Hill S, Kaplan N, Kuschnir E, Lexchin J, et al.: World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension.

    J Hypertens 2003, 21(11):1983-1992. OpenURL

  32. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses.

    The Am J Human Genetics 2007, 81(3):559-575. OpenURL

  33. Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps.

    Bioinformatics 2005, 21(2):263-265. OpenURL

  34. Burkett K, Graham J, McNeney B: Hapassoc: software for likelihood inference of trait associations with SNP haplotypes and other attributes.

    J Stat Softw 2006, 16(2):1-19. OpenURL

  35. Dahabreh IJ, Kitsios GD, Kent DM, Trikalinos TA: Paraoxonase 1 polymorphisms and ischemic stroke risk: a systematic review and meta-analysis.

    Genet Med 2010, 12(10):606-615. OpenURL

  36. Leviev N, Righetti A, James RW: Paraoxonase promoter polymorphism T(−107)C and relative paraoxonase deficiency as determinants of risk of coronary artery disease.

    J Mol Med 2001, 79(8):457-463. OpenURL

  37. Deakin S, Leviev I, Brulhart-Meynet MC, James RW: Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position-107, implicating the Sp1 transcription factor.

    Biochem Jl 2003, 372:643-649. OpenURL

  38. Demirdogen BC, Demirkaya S, Turkanoglu A, Bek S, Arinc E, Adali O: Analysis of paraoxonase 1 (PON1) genetic polymorphisms and activities as risk factors for ischemic stroke in Turkish population.

    Cell Biochem Funct 2009, 27(8):558-567. OpenURL

  39. Karakaya A, Ibis S, Kural T, Kose SK, Karakaya AE: Serum paraoxonase activity and phenotype distribution in Turkish subjects with coronary heart disease and its relationship to serum lipids and lipoproteins.

    Chemico-Biol Interact 1999, 118(3):193-200. OpenURL

  40. Brophy VH, Hastings MD, Clendenning JB, Richter RJ, Jarvik GP, Furlong CE: Polymorphisms in the human paraoxonase (PON1) promoter.

    Pharmacogenetics 2001, 11(1):77-84. OpenURL

  41. Brophy VH, Jampsa RL, Clendenning JB, McKinstry LA, Jarvik GP, Furlong CE: Effects of 5 ' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression.

    Am J Hum Genetics 2001, 68(6):1428-1436. OpenURL

  42. Hofer SE, Bennetts B, Chan AK, Holloway B, Karschimkus C, Jenkins AJ, Silink M, Donaghue KC: Association between PON 1 polymorphisms, PON activity and diabetes complications.

    Jf Diabetes Complicats 2006, 20(5):322-328. OpenURL

  43. Leviev I, James RW: Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations.

    Arterioscler Thromb Vasc Biol 2000, 20(2):516-521. OpenURL

  44. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, et al.: Assessing the impact of population stratification on genetic association studies.

    Nat Genet 2004, 36(4):388-493. OpenURL

  45. Du R: Genetics of Chinese population.

    Beijing Sci Publish 2004, 10:414-419. OpenURL

  46. Wang X, Fan Z, Huang J, Su S, Yu Q, Zhao J, Hui R, Yao Z, Shen Y, Qiang B, et al.: Extensive association analysis between oolymorphisms of PON gene cluster with coronary heart disease in Chinese Han population.

    Arterioscle Tthromb Vasc Biol 2003, 23(2):328-334. OpenURL

  47. Lash TL, Lien EA, Sørensen HT, Hamilton-Dutoit S: Genotype-guided tamoxifen therapy: time to pause for reflection?

    Lancet Oncol 2009, 10(8):825-833. OpenURL

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