Share This Article:

Paraoxonase 2 Gene (Cys311-Ser) Polymorphism and the Risk of Coronary Artery Disease

Abstract Full-Text HTML Download Download as PDF (Size:2615KB) PP. 465-475
DOI: 10.4236/wjcd.2014.49056    2,427 Downloads   2,972 Views  


Background: Human paraoxonase-2(PON2) which is exclusively intracellular possesses unique properities that distinguish it from PON1 and PON3. Recently, it was demonstrated that PON2 protects against atherosclerosis by preventing LDL oxidation. Emerging evidences have proposed that genetic variations in the PON2 gene may be associated with coronary artery disease (CAD). Objectives: To investigate the relationship between a common PON2 gene (Cys311-Ser) polymorphism and the presence and extent of CAD. Methods: The study comprised 112 patients recruited from those undergoing coronary angiography for suspected CAD, who were divided according to the presence or absence of CAD into 2 groups Group I including 62 patients with CAD and Group II including 50 patients proved to have normal coronaries. All the subjects included in the study were genotyped for the (Cys311-Ser) polymorphism of PON2 gene using RCR-RFLP. Results: The frequency of Cys allele was significantly higher in group I compared to Group II (77.4% vs. 56% respectively, P < 0.01). Patients with vessel score 3 had significantly higher severity score and higher Cys allele frequency than patients with vessel score 2, the latter group had also significantly higher severity score and Cys allele frequency than patients with vessel score 1. In multivariate logistic regression analysis of different variables for prediction of CAD, age [OR 3.79, CI (1.33 - 12.7), P < 0.01], smoking [OR 0.71, CI (0.23 - 7.81), P < 0.001], and PON2311 Cys allele [OR 5.67, CI (1.99 - 14.77), P < 0.001] were significantly independent predictors of CAD. Conclusion: Cys allele of PON2 311 gene polymorphism is an independent risk factor for CAD and it is associated not only with the presence of CAD but also with its extent and severity.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Elnoamany, M. , Dawood, A. and Azmy, R. (2014) Paraoxonase 2 Gene (Cys311-Ser) Polymorphism and the Risk of Coronary Artery Disease. World Journal of Cardiovascular Diseases, 4, 465-475. doi: 10.4236/wjcd.2014.49056.


[1] Guxens, M., Tomas, M., Elosua, R., Aldasoro, E., Segura, A., Fiol, H., Sala, J., Vila, J., Fullana, M., Senti, M., Vega, G., Rica, M., Marrugat, J. and The IBERICA Study Research Group (2008) Association between Paraoxonase-1 and Paraoxonase-2 Polymorphism and the Risk of Acute Myocardial Infarction. Revista Espanola de Cardiología, 61, 269-75.
[2] Jalilian, A., Javadi, E., Akrami, M., Fakhradeh, H., Heshmat, R., Rahmani, M. and Bandarian, F. (2008) Association of Cys311Ser Polymorphism of Paraoxonase-2 Gene with the Risk of Coronary Artery Disease. Archives of Iranian Medicine, 11, 544-549.
[3] Porntadavity, S., Permpongapaiboon, T. and Sukketsiri, W. (2010) Mini Review: Human Paraoxonase 2. EXCLI Jour-nal, 9, 159-172.
[4] Ng, C., Hama, S., Bourquard, N., Navab, M. and Peddy, S. (2006) Adenovirus-Mediated Expression of Human Paraoxonase-2 Protects against the Development of Atherosclerosis in Apolipoprotein-E Deficient Mice. Molecular Genetics and Metabolism, 89, 368-373.
[5] Horke, S., Witte, I., Wilgenbus, P., Kruger, M., Strand, D. and Forsterman, U. (2007) Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress-Induced Caspase Activation. Circulation, 115, 2055-2064.
[6] Mackness, B., Mcelduff, P. and Mackness, M. (2005) The Paraoxonase-2 310 Polymorphism Is Associated with the Presence of Microvascular Complications in Diabetes Mellitus. Journal of Internal Medicine, 258, 363-368.
[7] Chen, Q., Reis, S., Kammerer, C., McNamara, D., Holubkov, R. and Sharaf, B. (2003) Association between the Severity of Angiographic Coronary Artery Disease and Paraoxonase Gene Polymorphisms in the National Heart, Lung and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. The American Journal of Human Genetics, 72, 13-22.
[8] Helfand, M., Buckley, D.I., Freeman, M., Fu, R.W., Rogers, K., Fleming, C. and Humphrey, L.L. (2009) Emerging Risk Factors for Coronary Heart Disease: A Summary of Systematic Reviews Conducted for the US Preventive Services Task Force. Annals of Internal Medicine, 151, 496-509.
[9] Iqbal, M., Khan, A., Mehboobail, N. and Iqbal, S. (2007) Human Paraoxonase and HDL-Cholesterol in Pakistani Patients with Acute Myocardial Infarction and Normal Healthy Adults. Pakistan Journal of Medical Sciences, 23, 659-664.
[10] Niemiec, P., Zak, I. and Wita, K. (2007) The 242 T Variant of the CYBA Gene Polymorphism Increases the Risk of Coronary Artery Disease Associated with Cigarette Smoking and Hypercholesterolemia. Coronary Artery Disease, 18, 339-346.
[11] Schiller, N.B., Shah, P.M., Crawford, M., DeMaria, A., Devereux, R., Feigenbaum, H., Gutgesell, H., Reichek, N., Sahn, D., Schnittger, I., Silverman, N.H. and Tajik, A.J. (1989) Recommendations for Quantitation of the Left Ventricle by 2-Dimensional Echocardiography. Journal of the American Society of Echocardiography, 2, 358-367.
[12] Yvorchuk, K.J., Davies, R.A. and Chang, K.L. (1994) Measurement of Left Ventricular Ejection Fraction by Acoustic Quantification and Comparison with Radionuclide Angiography. American Journal of Cardiology, 74, 1052-1056.
[13] Reiber, J.H., Serruys, P.W., Kooijman, C.J., Wijns, W., Slager, C.J., Gerbrands, J.J., Schuurbiers, J.C., den Boer, A. and Hugenholtz, P.G. (1985) Assessment of Short-, Medium-, and Long-Term Variations in Arterial Dimensions from Computer-Assisted Quantitation of Coronary Cineangiograms. Circulation, 71, 280-288.
[14] Levinson, M.M. (2007) Leaning Center for Coronary Angiography. The Heart Surgery Forum. Cardiothorac Multimedia J, 54, 534-539.
[15] Schulze, M.B., Shai, I., Rimm, E.B., Li, T., Rifai, N. and Hu, F.B. (2005) Adiponectin and Future Coronary Heart Disease Events among Men with Type 2 Diabetes. Diabetes, 54, 534-539.
[16] Wolk, R., Berger, P., Lennon, R.J., Brilakis, E.S. and Somers, V.K. (2003) Body Mass Index: A Risk Factor for Unstable Angina and Myocardial Infarction in Patients with Angiographically Confirmed Coronary Artery Disease. Circulation, 108, 2206-2211.
[17] Meiattini, F., Kim, Y., Peroni, O. and Fryer, L. (1978) The 4-Hydroxybenzoate 14 Amino Phenazone Chromagenic System. Clinical Chemistry, 24, 2161-2165.
[18] Fossati, P. and Prenciphe, L. (1982) Determination of Serum Triglyceride. Clinical Chemistry, 28, 2077-2080.
[19] Gordon, T., Castelli, W.P., Huortland, M.C., Kannel, W.B. and Dawber, T.R. (1977) High Density Lipoprotein as a Protective Factor against Coronary Heart Disease. The Framingham Study. American Journal of Medicine, 62, 707-714.
[20] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge. Clinical Chemistry, 18, 499-502.
[21] Miller, S.A., Dykes, D.D. and Polesky, H.F. (1989) A Simple Salting out Procedure for Extracting DNA from Human Nucleated Cells. Nucleic Acids Research, 16, 1215.
[22] Lerman, A. and Zeiher, A. (2005) Endothelial Function: Cardiac Events. Circulation, 111, 363-368.
[23] Lavi, S., Mc Connell, J., Lavi, R., Barsness, G., Rihal, C., Novak, G., Lerman, L. and Lerman, A. (2008) Association between the Paraoxonase-1 192 Q >R Allelic Variant and Coronary Endothelial Dysfunction in Patients with Early Coronary Artery Disease. Mayo Clinic Proceedings, 83, 158-164.
[24] Cohn, J., Quyyumi, A., Hollenberg, N. and Jamerson, K. (2004) Surrogate Markers for Cardiovascular Disease: Functional Maskers. Circulation, 109, IV31-IV46.
[25] Draganov, D. and La Du, B. (2004) Pharmacogenetics of Paraoxonasaes: A Brief Review. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369, 78-88.
[26] Gupta, N., Gill, K. and Singh, S. (2009) Paraoxonases: Structure, Gene Polymorphism & Role in Coronary Artery Disease. Indian Journal of Medical Research, 130, 361-368.
[27] Levy, E., Trudel, K., Bendayan, M., Seidman, E., Deluin, E., Elchebly, M., Lavoie, J.C., Precourt, L.P., Amre, D. and Sinnett, D. (2007) Biological Role, Protein Expression, Subcellular Localization and Oxidative Stress Response of Paraoxonase 2 in the Intestine of Humans and Rats. American Journal of Physiology. Gastrointestinal and Liver Physiology, 293, G1252-G1261.
[28] Wang, X., Fan, Z., Huang, J., Su, S., Yu, Q., Zhao, J., Hui, R., Yao, Z., Qiang, B. and Gu, D. (2003) Extensive Association Analysis between Polymorphism of PON Gene Cluster with Coronary Heart Disease in Chinese Han Population. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 328-334.
[29] Martinelli, N., Girelli, D., Olivieri, O., Stranieri, C., Trabetti, E., Pizzolo, F., Friso, S., Tenuti, I., Cheng, S., Grow, A., Pignatti, P. and Corrocher, R. (2004) Interaction between Smoking and PON2 Ser311Cys Polymorphism as Determinant of the Risk of Myocardial Infarction. European Journal of Clinical Investigation, 34, 14-20.
[30] Sanghera, D., Aston, C., Saha, N. and Kamboh, M. (1998) DNA Polymorphisms in Two Paraoxonase Genes (PON1 and PON2) Are Associated with the Risk of Coronary Heart Disease. American Journal of Human Genetics, 62, 36-44.
[31] Leus, F., Zwart, M., Kastelan, J. and Voorbij, H. (2001) PON2 Gene Variants Are Associated with Clinical Manifestations of Cardiovascular Disease in Familial Hypercholesterolemia Patients. Atherosclerosis, 154, 641-649.
[32] Pan, J., Lai, S., Chiang, S., Chou, S. and Chiang, A. (2002) The Risk of Coronary Artery Disease in Population of Taiwan Is Associated with Cys-Ser 311 Polymorphism of Human Paraoxonase (PON)-2 Gene. Chinese Medical Journal (Taipei), 65, 415-421.
[33] Robertson, K., Hawe, E., Miller, G., Talmud, P. and Humphries, S. (2003) Human Paraoxonase Gene Cluster Polymorphisms as Predictors of Coronary Heart Disease Risk in the Prospective Northwick Park Heart Study II. Biochimica et Biophysica Acta, 1639, 203-212.
[34] Wheeler, J., Keavney, B., Watkins, H., Collins, R. and Danesh, J. (2004) Four Paraoxonase Gene Polymorphism in 11212 Cases of Coronary Heart Disease and 12786 Controls: Meta-Analysis of 43 Studies. Lancet, 363, 689-695.
[35] Souza, E., Hirata, R., Santos, F., Piccioti, R., Lucchessi, A., Silbiger, V., Rodrigues, A., Sampaio, M., Armagnijan, D., Salem, M., Doi, S. and Hirata, M. (2008) Paraoxonase Polymorphisms Are Associated with Nitrate Levels and Vascular Response in Young Adults with Myocardial Infarction. American Journal of Medicine, 3, 146-154.
[36] Chi, D.S., Ling, W.H., Ma, J., Xia, M., Hou, M.J., Wang, Q., Zhu, H.L., Tang, Z.H. and Yu, X.P. (2006) Relationship between Paraoxonase 1 55 Met/Leu, Paraoxonase 2 148 Ala/Gly Genetic Polymorphisms and Coronary Artery Disease. Chinese Journal of Medical Genetics, 23, 289-293.
[37] Shin, B. (2009) Paraoxonase Gene Polymorphism in South-Western Korean Population. Journal of Korean Medical Science, 24, 561-566.
[38] Thameem, F., He, X., Voruganti, S., Nath, S., Fanti, P., Blangero, J., Mac Cluer, J., Comuzzie, A., Arar, N. and Abboud, H. (2009) Evaluation of Polymorphisms in Paraoxonase 2 (PON2) Genes and Their Association with Cardiovascular-Renal Disease Risk in Mexican Americans. Kidney and Blood Pressure Research, 32, 200-204.
[39] Bayrak, T., Bayrak, A., Volkan-Salanci, B., Deniz, A., Tokgozoglu, S., Yavuz, B., Alikasifoglu, M. and Demirpence, E. (2012) Relationship of PON2 Gene Ser311Cys Polymorphism and Serum Paraoxonase Activity with Coronary Artery Disease in Turkish Population. Turkish Journal of Biochemistry, 37, 150-155.
[40] Ng, C., Bourquard, N., Grijalva, V., Hama, S., Shih, D., Navab, M., Fogelman, A., Lusis, A., Young, S. and Reddy, S. (2006) Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B Containing Lipoproteins: Anti-Atherogenic Role for Paraoxonase-2. Journal of Biological Chemistry, 281, 29491-29500.
[41] Imai, Y., Morita, H., Kurihara, H., Sugiyama, T., Kato, N., Ebihara, A., Hamada, C., Kurihara, Y., Shindol, T., Oh-hasi, Y. and Yazaki, Y. (2000) Evidence for Association between Paraoxonase Gene Polymorphisms and Atherosclerotic Diseases. Atherosclerosis, 149, 435-442.
[42] Draganov, D., Teiber, J., Speelman, A., Osawa, Y., Sunahara, R. and La Du, B. (2005) Human Paraoxonases (PON1, PON2 and PON3) Are Lactonases with Overlapping and Distinct Substrate Specificities. Journal of Lipid Research, 46, 1239-1247.
[43] Shiner, M., Fuhrman, B. and Aviram, M. (2004) Paraoxonase 2 (PON2) Expression Is up Regulated via a Reduced Nicotinamide-Adenine-Dinucleotide-Phosphate(NADPH)-Oxidase-Dependent Mechanism during Monocyte Differentiation Macrophages. Free Radical Biology and Medicine, 37, 2052-2063.

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.