20Jul 2017

THE IMPACT OF RS662 GENOTYPING ON THE SERUM ACTIVITY OF THE PARAOXONASE -1 ENZYME IN IRAQI PATIENTS WITH CARDIOVASCULAR DISEASES.

  • B. SC., Higher Diploma, Ministry of Health, Kimadia, Baghdad, Iraq.
  • Professor, PhD, Clinical Biochemistry, College of Medicine, Al Nahrain University, Baghdad, Iraq.
  • Lecturer, MB ChB - FIBMS, Consultant Cardiologist, Medicine-Cardiology ,College of Medicine, , Al Nahrain University, Baghdad, Iraq.
Crossref Cited-by Linking logo
  • Abstract
  • Keywords
  • References
  • Cite This Article as
  • Corresponding Author

Background: Cardiovascular diseases (CVDs) are diseases that affect the heart or vessels. Coronary artery disease (CAD) and peripheral (PAD) are types of CVD. PON1 is a HDL-associated lipolactonase is considered to be atheroprotective by preventing LDL and cell membranes oxidation. A common polymorphism due to an amino acid substitution (Glutamine  Arginine) at codon 192 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1192 polymorphism is an independent risk factor for CVD Objectives: The effect of the PON1 activity and PON1 Q192R (rs662) polymorphisms on the CVD include patients with PAD and CAD. Subject and Methods: This case control study consisted of 180 subjects were divided into 100 patients with CVD (50 patients with PAD and 50 patients with CAD), and 80 healthy controls. Serum levels for lipid profile and PON1 enzyme were measured by spectrophotometer using paraoxon as a substrate. The genetic polymorphism of PON1 was detected by TaqMan-based allele discrimination RT- PCR Results: The means ?SEM of serum PON1 activity were highly significantly decreased in PAD and CAD as compared to control group. The heterozygote (Q192R) genotype of PON1 polymorphism is abundant among all of the studied groups (68%for PAD, 56% for CAD and 65%for control, respectively) . The CAD patients carry the high risk RR genotyping (odd ratio of 2.69, with the confidence interval of (1.12-6.47; p=0.02).The PAD who carry the RR genotype have a risk ratio 1.57 at confidence interval of 0.61- 4.02. Conclusion: Reduction of PON1 activity is one of the risk factor of development of CVD . Patients who carry the RR genotyping were at high risk to develop CVD. Our results indicate that controversial relationships regarding the PON1 rs 662 (Q192R) polymorphism and CVD. Serum PON1 activity is more informative than the PON1 genotype in evaluating the severity and extent of cardiovascular disease in Iraqi patients.


  1. Adkins S, Gan KN, Mody M, La Du BN.(1991): Molecular basis for the polymorphic forms of human serum paraoxonase/ arylesterase: glutamine or arginine at position 192, for the respective A or B allozymes. Am J Hum Genet .,40:277?82.
  2. Aldridge WN (1953): Serum esterases. I. Two types of esterase (A and B) hydrolysing p-nitrophenyl acetate,propionate and butyrate, and a method for their determination. Biochem J., 53: 110?117.
  3. Altuner D, Suzen SH, Ates I, Koc GV, Aral Y, Karakaya A.(2011): Are PON1, Q/R 192 and M/L 55 polymorphisms risk factors for diabetes complications in a Turkish population? Clin Biochem. , 44:372-376.
  4. Biggs AI.(1954): A spectrophotometric determination of the dissociation constants of p-nitrophenol and papaverine. Trans Faraday Soc., 50:800-802.
  5. Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, La Du BN (2000): Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos, 28(11):1335-1342.
  6. Blatter Garin MC, Moren X, James RW (2006): Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I. J Lipid Res., 47(3):515-520.
  7. Bounafaa A, Berrougui H, Ghalim N, Nasser B, Bagri A, Moujahid A, Ikhlef S, Camponova P, Yamoul N , Simo OK , Essamadi A, Khalil A((2015): Association between Paraoxonase-1 (PON1) Polymorphisms and the Risk of Acute Coronary Syndrome in a North African Population. PLoS One,10 (8): e0133719.
  8. Chistiakov DA, Melnichenko AA ,Orekhov AN, Bobryshev YV.(2017): Paraoxonase and atherosclerosis related cardiovascular diseases. Biochimie, 132: 19-27.
  9. Cohen E, Aviram M, Khatib S, Volkova? N, Vaya? J (2016): Human carotid atherosclerotic plaque protein(s) change HDL protein(s) composition and impair HDL anti-oxidant activity. BioFactors, 42: 115?128.
  10. Costa LG, Cole TB, Jarvik GP & Furlong CE.( 2003): Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism. Annu Rev Med., 54: 371?392.
  11. Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J and Furlong CE (1996): The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 14: 334 ?336.
  12. Dell?Omo G, Penno G, Pucci L, Lucchesi D, Prato SD, Pedrinelli R (2014):Q192R Paraoxonase (PON)1 Polymorphism, Insulin Sensitivity, and Endothelia Function in Essential Hypertensive Men. Clin Med Insights , 8:1-11.
  13. Deakin SP, James RW (2004): Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci.,107:435?447.
  14. Du XM, Kim MJ, Hou L, Le Goff W, Chapman MJ, Van Eck M, Curtiss LK, Burnett JR, Cartland SP, Quinn CM, Kockx M, Kontush A, Rye KA, Kritharides L, Jessup W (2015): HDL particle size is a critical determinant of ABCA1-mediated macrophage cellular cholesterol export. Circ Res., 116(7): 1133?1142.
  15. Durrington N.P., Mackness B., and Mackness I.M.( 2001). Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol., 21( 4) :473?480.
  16. Friedewald WT, Levy RI, Fredrickson DS (1972): Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem.,18:499?502.
  17. Gaidukov L, Rosenblat M, Aviram M, Tawfik DS (2006): The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux. J Lipid Res. ,47(11):2492-502.
  18. Genest J, Frohlich J, Fodor G, McPherson R (2003): Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: CMAJ.,169(9):921?924.
  19. Gran?r M, James RW, Kahri J, Nieminen MS, Syv?nne M, Taskinen M R (2006): Association of Paraoxonase-1 Activity and Concentration With Angiographic Severity and Extent of Coronary Artery Disease. Journal of the American College of Cardiology,47(12):2429-2435.
  20. Hern?ndez-D?az Y, Tovilla-Z?rate CA, Ju?rez-Rojop IE, Gonz?lez-Castro TB, Rodr?guez-P?rez C, L?pez-Narv?ez ML, Rodr?guez-P?rez JM, C?mara-?lvarez JF (2016): Effects of paraoxonase -1 gene polymorphisms on heart diseases: Systematic review and meta-analysis of 64 case-control studies.Medicine (Baltimore)., (44):e5298.
  21. Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS (2004):Structure and evolution of the serum paraoxonase family of detoxifying and antiatheroscleroticenzymes. Nat Struct Mol Biol., 11(5): 412?419.
  22. Ivanova EA , Orekhov AN (2016):The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis. Int J Mol Sci,17(2):193.
  23. Kallel A, Sediri Y, Sbai MH, Mourali MS, Feki M, Elasmi M, Taieb SH, Sanhaji H, Souheil O,Mechmeche R, Jemaa R (2010):The paraoxonase L55M and Q192R gene polymorphisms and myocardial infarction in a Tunisian population. Clin Bio chem.,43(18): 1461?1463.
  24. Kasprzak M P, Iskra M , Majewski W, Napierala B M, Gryszczynska B,Strzyzewski? K, Kasprzak? J (2014): PON1 status evaluation in patients with chronic arterial occlusion of lower limbs due to atherosclerosis obliterans. Archives of Medical Science, 10(6):1101-1108.
  25. Kowalska K, Socha E, Milnerowicz H.(2015): The role of paraoxonase in cardiovascular diseases.Ann Clin Lab Sci.,45(2):226-33.
  26. Krisch, K. (1968): Enzymatische Hydrolyse von Di?thyl-p-nitrophenylphosphat (E 600) durch menschliches Serum. Clin Chemi Lab Medi., 6(1), pp.41-45.
  27. Kumar A, Mash B, Rupesinghe G.(2007): Peripheral arterial disease - high prevalence in rural black South Africans. S Afr Med J., 97(4):285-288.
  28. Lakshmy R, Ahmad D, Abraham RA, Sharma M, Vemparala K, Das S, Reddy KS, Prabhakaran D (2010): Paraoxonase gene Q192R & L55M polymorphisms in Indians with acute myocardial infarction & association with oxidized low density lipoprotein. Indian J Med Res. ,131:522-529.
  29. Lawlor DA, Day IN, Gaunt TR, Hinks LJ, Briggs PJ, Kiessling M, et al. (2004):The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women's Heart and Health cohort study and a meta-analysis. BMC Genet.,5:17?17.
  30. Lebedy D, Kafoury M, Haleem D, Ibrahim A, Awadallah E, Ashmawy I? (2014): Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus. J Diabetes Metab Disord., 13(1):124.
  31. Luersen K, Schmelzer C, Boesch-Saadatmandi C, Kohl C, Rimbach G, Doring F (2011): Paraoxonase 1 polymorphism Q192R affects the pro-inflammatory cytokine TNF-alpha in healthy males. BMC ResNotes 4: 141.
  32. Luu HN, Kingah PL, North K, Boerwinkle E, Volcik KA ( 2011): Interaction of folate intake and the paraoxonase Q192R polymorphism with risk of incident coronary heart disease and ischemic stroke: the atherosclerosis risk in communities study. Ann Epidemiol., 21(11):815?823.
  33. Mackness MI, Arrol S, Durrington PN ( 1991): Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. ,286(1-2):152-154.
  34. Mackness MI, Arrol S, Abbott CA, Durrington PN.( 1993): Is paraoxonase related to atherosclerosis. Chem Biol Interact, 87(13):161?171.
  35. Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA (1996): Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol .,7(2):69?76.
  36. Mackness M, Mackness B( 2014): Current Aspects of Paraoxonase-1 Research. In: Tsugikazu . The HDL Handbook: Biological functions and clinical implications. 2nd ed? Academic Press, Chapter (11) pages 273?291.
  37. Mart?nez-Quintana E, Rodr?guezGonz?lez F, Medina-Gil JM, Garay-S?nchez P, Tugores A (2017): Paraoxonase- 1 (Q192R) gene polymorphism, coronary heart disease and the risk of a new acute coronary event. Clin Investig Arterioscler. , 29(1):1-6.
  38. Norgren, L,Hiatt, W R, Dormandy, J A,Nehler, M R,Harris, K A,Fowkes, F G R(2007): Inter-Society Consensus for the Management of Peripheral Arterial Disease ( TASC II ). J Vasc Surg,45(1):s5-s67
  39. Ombres D, Pannitteri G, Montali A, Candeloro A, Seccareccia F, Campagna F, Cantini R, Campa PP, Ricci G and Arca M (1998)?: The gln-Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in italian patients.?Arterioscler Thromb Vasc Biol18: 1611?1616.
  40. Paapstel, K.Zilmer, M.Eha, J.Tootsi, K.Piir, A.Kals, J.(2016): Association Between Fibulin-1 and Aortic Augmentation Index in Male Patients with Peripheral Arterial Disease. Eur J Vasc Endovasc Surg ,51(1); 76-82.
  41. Pr?court LP, Amre D, Denis MC, Lavoie JC, Delvin E, Seidman E, Levy E.(2011): The three-gene paraoxonase family:physiologic roles, actions and regulation. Atherosclerosis , 214(1): 20?36.
  42. Primo-Parma SL, Sorenson? RC, Teiber J, La Du? BN (1996): The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 33, 498?509.
  43. Rainwater DL, Rutherford S, Dyer TD, Rainwater ED, Cole SA, Vandeberg JL, Almasy L, Blangero J, Maccluer JW, Mahaney MC ( 2009): Determinants of variation in human serum paraoxonase activity. Heredity (Edinb),102:147?154.
  44. Rodr?guez-Esparrag?n F, Rodr?guez-P?rez JC, Hern?ndez-Trujillo Y, Mac?as-Reyes A, Medina A, Caballero A, Ferrario CM (2005):Allelic variants of the human scavenger receptor class B type 1 and paraoxonase 1 on coronary heart disease: genotypephenotype correlations. Arterioscler Thromb Vasc Biol.,25:854?860.
  45. Rozek LS, Hatsukami TS, Richter RJ, Ranchalis J, Nakayama K, McKinstry, LA, Gortner DA , Boyko E, Schellenberg GD, Furlong CE, Jarvik GP (2005): The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status. Journal of Lipid Research, 46(9):1888-1895.
  46. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CH JL (2015): Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med . ,372:1333-1341.
  47. Scherrer DZ, de Souza Zago V H,Vieira IC, Parra ES, Panzoldo ?NB, Alexandre F, Secolin R, Baracat J,Rocha Quintao EC, de Faria, EC (2015): p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample. Arquivos Brasileiros De Cardiologia, 105(1):45-52.
  48. Sent? M, Tom?s M, Marrugat J, Elosua R, Investigators R (2001): Paraoxonase1-192 Polymorphism Modulates the Nonfatal Myocardial Infarction Risk Associated With Decreased HDLs. Arterioscler Thromb Vasc Biol., 21:415-420.
  49. Thiruvoipati T, Kielhorn CE, Armstrong EJ (2015):Peripheral artery disease in patients with diabetes : Epidemiology,mechanisms,and outcomes. World J Diabetes ,6(7):961-969.
  50. Zargari M, Sharafeddin ?F, Mahrooz A, Alizadeh A, Masoumi P (2016): The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes. Exp Biol Med (Maywood)., 241(14):1489-96.
  51. World Health Organization(WHO): Regional Office for Southeast Asia. Hypertension fact sheet. Last accessed at http://www.searo.who.int/linkfiles/non_communicable_diseases_hypertension-fs.pdf . April 2012.
  52. World Health Organization (WHO):Cardiovascular Diseases (CVDs), Factsheet: (Accessed on 2015 May 02). Available online: http://www.who.int/mediacentre/factsheets/fs317/en/.

[Raya Kamal Mohammed Salih, Najat Abdulrazzaq Hasan and Rafid Bashir Hashim. (2017); THE IMPACT OF RS662 GENOTYPING ON THE SERUM ACTIVITY OF THE PARAOXONASE -1 ENZYME IN IRAQI PATIENTS WITH CARDIOVASCULAR DISEASES. Int. J. of Adv. Res. 5 (Jul). 825-835] (ISSN 2320-5407). www.journalijar.com


Raya Kamal mohammed Salih
Ministry of Health-KIMADIA

DOI:


Article DOI: 10.21474/IJAR01/4786      
DOI URL: http://dx.doi.org/10.21474/IJAR01/4786