Q192R and L55M polymorphism in paraoxonase 1 gene in patients with coronary heart disease of different age and sex

Evidence for genetic polymophisms may contribute to the dependence on sex and age differences in biochemical phenotypes, clinical manifestation, severity and success in medical treatment of coronary artery disease (CAD) comes from a variety of studies. Two genetic polymorphisms, L55M and Q192R, in the human antioxidant system paraoxonase 1 gene (PON1) have been shown to be associated with increased risk of CAD. The aim of recent study was to investigate a possible association between polymorphic variants of PON1 and CAD in patients of different age and sex. The group of patients with CAD (323 men and 71 women) and the group of healthy (114 men and 84 women) randomly sampled from St Petersburg were investigated clinically, biochemically and genetically. We found out the genotype L55M and Q192R frequencies in the group of patients with CAD were different depending on sex and age (p = 0,057, p = 0,007). In women with CAD the frequency of 55MM genotype (ОR = 2,1311, 95 % CI 1,14-3,98) was significantly higher and the frequency of 192QR genotype (ОR = 0,59, 95 % CI 0,39-0,89) was significantly lower than in men with CAD who survived myocardial infarction (MI) under the age of 45. Our results suggest that both PON1 polymorphisms play the role in risk of CAD. Furthermore, PON1 polymorphisms act in various ways in patients of different age and sex.

paraoxonase, genetic polymorphism, coronary artery disease, antioxidant system

1. Оганов Р.Г., Масленникова Г.Я. Развитие профилактической кардиологии в России. Кардиоваскулярная терапия и профилактика. 2004;3:11-14.

2.

3. Галявич А.С., Салахова Л.Р. Нарушения обмена жирных кислот при атеросклерозе и возможности его коррекции. Кардиология. 2006;12:36-39.

4.

5. Липовецкий Б.М., Шестов Д.В. и др. Эпидемиологические аспекты ишемической болезни сердца, артериальной гипертонии и атерогенных изменений липидного состава крови у мужчин и женщин Ленинграда 20-69 лет. Тер. арх. 1984:44-48.

6.

7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Circulation 2002.

8.

9. La Du BN, Aviram M, Billecke S, Navab M, Primo-Parmo S, Sorenson RC, et al. On the physiological role(s) of the paraoxonases. Chemico-Biological Interactions. 1999;119-120:379-88.

10.

11. Mackness B, Durrington PN, Mackness MI. The paraoxonase gene family and coronary heart disease. Curr Opin Lipidol. 2002 Aug;13(4):357-62.

12.

13. Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 1991;286:152-4

14.

15. 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;101:1581-90.

16.

17. Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, уе al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 2000;41:1495-508.

18.

19. Saha N, Roy AC, Teo SH, Tay JSH, Ratnam SS. Influence of serum paraoxonase polymorphism in serum lipids and apolipoproteins. Clin Genet. 1991;40:277-82.

20.

21. Deakin S, James R. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci. 2004;107:435-47.

22.

23. Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN. Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low lipoprotein oxidative modification. FEBS.Lett. 1998;423(1):57-60.

24.

25. Scacchi R, Corbo RM, Rickards O, De Stefano GF. New data on the world distribution of paraoxonase (PON1 Gln 192-Arg) gene frequencies. Hum Biol. 2004 Jun;75(3):365-73.

26.

27. Cherki M, Berrougui H, Isabelle M, Cloutier M, Koumbadinga GA, Khalil A. Effect of PON1 polymorphism on HDL antioxidant potential is blunted with aging. Exp Gerontol. 2007 Aug;42(8):815-24.

28.

29. Playfer JR, Eze LC, Bullen MF, Evans DAP. Genetic polymorphism and interethnic variability of plasma paraoxonase activity. J Med Genet. 1976;13:337-342.

30.

31. Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993;3:73-6.

32.

33. Adkins S, Gan KN, Mody M, La Du B. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine for arginine at position 191, for the respective A or B allozymes. Am J Hum Genet. 1993;52:598-608.

34.

35. Gene Database SNPs: http:pga.gs.washington.edu

36.

37. Clendenning JB, Humbert R, Green ED, Wood C, Traver D, Furlong CE./ Structural organization of the human PON1 gene. Genomics. 1996 Aug 1;35(3):586-9.

38.

39. Van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF. The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine. Neth J Med. 2006 Feb;64(2):34-8.

40.

41. Leviev L., Franco N., James R. Two alleles of the human paraoxonase gene produce different amounts of mRNA: an explanation for differences in serum concentrations of paraoxonase associated with the (Leu-Met54) polymorphisms. Arterioscler Thomb Vasc Biol. 1997;17:2935-9.

42.

43. Leviev I, Deakin S, James RW Decreased stability of the M54 isoform of paraoxonase as a contributory factor to variations in human serum paraoxonase concentrations. J Lipid Res. 2001 Apr;42(4):528-35.

44.

45. Roest M, van Himbergen TM, Barendrecht AB, Peeters PH, van der Schouw YT, Voorbij HA. Genetic and environmental determinants of the PON-1 phenotype. Eur J Clin Invest. 2007 Mar;37(3):187-96.

46.

47. Oliveira SA, Mansur AP, Ribeiro CC, Ramires JA, Annichino-Bizzacchi JM PON1 M/L55 mutation protects high-risk patients against coronary artery disease. Int J Cardiol. 2004 Mar;94(1):73-7.

48.

49. Fortunato G, Rubba P, Panico S, Trono D, Tinto N, Mazzaccara C, et al. A paraoxonase gene polymorphism, PON 1 (55), as an independent risk factor for increased carotid intima-media thickness in middle-aged women. Atherosclerosis. 2003 Mar;167(1):141-8

50.

51. Rea IM, McKeown PP, McMaster D, Young IS, Patterson C, Savage MJ, et al. Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis. Exp Gerontol. 2004 Apr;39(4):629-35.

52.

53. Martinelli N, Girelli D, Olivieri O, Stranieri C, Trabetti E, Pizzolo F, et al. Interaction between smoking and PON2 Ser311Cys polymorphism as a determinant of the risk of myocardial infarction. Eur J Clin Invest. 2004 Jan;34(1):14-20

54.

55. Gardemann A, Philipp M, Hess K, Katz N, Tillmanns H, Haberbosch W. The paraoxonase Leu-Met54 and Gln-Arg191 gene polymorphisms are not associated with the risk of coronary heart disease. Atherosclerosis. 2000 Oct;152(2):421-31.

56.

57. Kordonouri O, James RW, Bennetts B, Chan A, Kao YL, Danne T, Silink M, Donaghue K. Modulation by blood glucose levels of activity and concentration of paraoxonase in young patients with type 1 diabetes mellitus. Metabolism. 2001 Jun;50(6):657-60.

58.

59. Mackness B, Durrington PN, Abuashia B, Boulton AJ, Mackness MI. Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy. Clin Sci (Lond). 2000 Mar;98(3):355-63.

60.

61. Malin R, Loimaala A, Nenonen A, Mercuri M, Vuori I, Pasanen M, et al. Relationship between high-density lipoprotein paraoxonase gene M/L55 polymorphism and carotid atherosclerosis differs in smoking and nonsmoking men. Metabolism. 2001 Sep;50(9):1095-101.

62.

63. Hegele RA, Brunt JH, Connelly PW. A polymorphism of the paraoxonase gene associated with variation in plasma lipoproteins in a genetic isolate. Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):89-95.

64.

65. Pasqualini L, Cortese C, Marchesi S, Siepi D, Pirro M, Vaudo G, et al. Paraoxonase-1 activity modulates endothelial function in patients with peripheral arterial disease. Atherosclerosis. 2005 Dec;183(2):349-54.

66.

67. James RW, Leviev I, Ruiz J, Passa P, Froguel P, Garin MC. Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes. 2000 Aug;49(8):1390-3.

68.

69. Srinivasan SR, Li S, Chen W, Tang R, Bond MG, Boerwinkle E, et al. Q192R polymorphism of the paraoxanase 1 gene and its association with serum lipoprotein variables and carotid artery intima-media thickness in young adults from a biracial community. The Bogalusa Heart Study. Atherosclerosis. 2004 Nov;177(1):167-74.

70.

71. Chen Q, Reis SE, Kammerer CM, McNamara DM, Holubkov R, Sharaf BL, et al.; WISE Study Group. 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. Am J Hum Genet. 2003 Jan;72(1):13-22. Epub 2002 Nov 26.

72.

73. Christiansen L, Bathum L, Frederiksen H, Christensen K. Paraoxonase 1 polymorphisms and survival. Eur J Hum Genet. 2004 Oct;12(10):843-7.

74.

75. Aynacioglu AS, Kepekci Y. The human paraoxonase Gln-Argl92 (Q/R) polymorphism in turkish patients with coronary artery disease. Int J Cardiol. 2000 Jun 12;74(1):33-7.

76.

77. Ferre N, Tous M, Paul A, Zamora A, Vendrell JJ, Bardaji A, et al. Paraoxonase Gln-Arg(192) and Leu-Met(55) gene polymorphisms and enzyme activity in a population with a low rate of coronary heart disease. Clin Biochem. 2002;35:197-203.

78.

79. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Xia Yang, Schmitt D, et al. Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk. JAMA. 2008;299(11):1265-76.

80.

81. Gaidukov L, Rosenblat M, Aviram M, Tawfik DS. The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux. J Lipid Research. 2006;47(11):2492-502.

82.

83. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. М.: Медиа Сфера. 1998. с. 264-7.

84.