It is well known that serum paraoxonase (PON1) plays an important role in the protection of LDL from oxidation. PON1 55 polymorphism is currently investigated for its possible involvement in cardiovascular diseases. The objective of our study is to verify if PON1 55 polymorphism is associated with risk of acute coronary syndrome (ACS) and with biochemical myocardial ischemia markers, such as troponin I, creatine kinase (CK)-MB, myoglobin, and C-reactive protein. We analysed PON1 55 polymorphism in a total of 440 elderly patients who underwent an ACS episode: 98 patients affected by unstable angina (UA), 207 AMI (acute myocardial infarction) patients affected by STEMI (ST elevation), and 135 AMI patients affected by NSTEMI (no ST elevation). We found that individuals carrying PON1 55 LL genotype are significantly more represented among AMI patients affected by NSTEMI; moreover, the patients carrying LL genotype showed significantly higher levels of myoglobin in comparison to LM + MM carriers patients. Our study suggests that PON1 55 polymorphism could play a role in the pathogenesis of cardiac ischemic damage. In particular, the significant association between PON1 55 LL genotype and the occurrence of a NSTEMI may contribute to improve the stratification of the cardiovascular risk within a population. 1. Introduction In western developed countries the atherosclerosis-related diseases, such as cardiovascular disease (CVD), remains so far the major cause of morbidity and premature death [1]. For this reason, atherosclerotic cardiovascular disease represents a major public health concern, and many efforts are addressed to better understand the mechanisms underlying this important pathology. The oxidative modification of low-density lipoprotein (LDL) in the arterial wall is claimed to play a central role in the pathogenesis of atherosclerosis. The oxidative stress is demonstrated to increase the formation of oxidized macrophages which are, in turn, responsible for the oxidation of LDL. Early studies focused on atherosclerosis generally considered LDL as the main cause of this pathology, and the inclusion of statins in clinical practice has significantly improved the quality of life of patients. The hypothesis of the inflammation as an underlying cause of atherosclerosis has been proposed only recently. For a long time, these two aspects (lipids and inflammation) have been kept apart, but actually they are the two faces of the same medal and both should be considered when we deal with atherosclerosis. Serum paraoxonase (PON1), an HDL-associated enzyme, plays
References
[1]
P. M. Ridker, “Inflammation, atherosclerosis, and cardiovascular risk: an epidemiologic view,” Blood Coagulation and Fibrinolysis, vol. 10, no. 1, supplement, pp. S9–S12, 1999.
[2]
M. I. Mackness, S. Arrol, C. Abbott, and P. N. Durrington, “Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase,” Atherosclerosis, vol. 104, no. 1-2, pp. 129–135, 1993.
[3]
A. D. Watson, J. A. Berliner, S. Y. Hama et al., “Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein,” Journal of Clinical Investigation, vol. 96, no. 6, pp. 2882–2891, 1995.
[4]
C. Zhang, W. Peng, M. Wang et al., “Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein e knockout mice,” Gene Therapy, vol. 17, no. 5, pp. 626–633, 2010.
[5]
R. Humbert, D. A. Adler, C. M. Disteche, C. Hassett, C. J. Omiecinski, and C. E. Furlong, “The molecular basis of the human serum paraoxonase activity polymorphism,” Nature Genetics, vol. 3, no. 1, pp. 73–76, 1993.
[6]
S. Adkins, K. N. Gan, M. Mody, and B. N. La Du, “Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes,” American Journal of Human Genetics, vol. 52, no. 3, pp. 598–608, 1993.
[7]
M. C. Garin, R. W. James, P. Dussoix et al., “Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes,” Journal of Clinical Investigation, vol. 99, no. 1, pp. 62–66, 1997.
[8]
J. G. Wheeler, B. D. Keavney, H. Watkins, R. Collins, and J. Danesh, “Four paraoxonase gene polymorphisms in 11212 cases of coronary hearth disease and 12786 controls: meta-analysis of 43 studies,” Lancet, vol. 363, pp. 689–695, 2004.
[9]
J. S. Alpert, K. Thygesen, E. Antman, and J. P. Bassand, “Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee f or the redefinition of myocardial infarction,” Journal of the American College of Cardiology, vol. 36, no. 3, pp. 959–969, 2000.
[10]
Guidelines Committee, “European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension,” Journal of Hypertension, vol. 21, pp. 1011–1053, 2003.
[11]
R. Kahn, “Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,” Diabetes Care, vol. 20, no. 7, pp. 1183–1197, 1997.
[12]
S. A. Miller, D. D. Dykes, and H. F. Polesky, “A simple salting out procedure for extracting DNA from human nucleated cells,” Nucleic Acids Research, vol. 16, no. 3, p. 1215, 1988.
[13]
M. Bonafè, F. Marchegiani, M. Cardelli et al., “Genetic analysis of paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians,” European Journal of Human Genetics, vol. 10, no. 5, pp. 292–296, 2002.
[14]
F. Marchegiani, M. Marra, F. Olivieri et al., “Paraoxonase 1: genetics and activities during aging,” Rejuvenation Research, vol. 11, no. 1, pp. 113–127, 2008.
[15]
Y. Wang, W. Fu, F. Xie et al., “Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population,” Journal of Human Genetics, vol. 55, no. 8, pp. 490–494, 2010.
[16]
S. Agrawal, G. Tripathi, R. Prajnya et al., “Paraoxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians,” Indian Journal of Medical Sciences, vol. 63, no. 8, pp. 335–344, 2009.
[17]
R. Malin, A. Loimaala, A. Nenonen et al., “Relationship between high-density lipoprotein paraoxonase gene M/L55 polymorphism and carotid atherosclerosis differs in smoking and nonsmoking men,” Metabolism, vol. 50, no. 9, pp. 1095–1101, 2001.
[18]
K. S. Robertson, E. Hawe, G. J. Miller, P. J. Talmud, and S. E. Humphries, “Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II,” Biochimica et Biophysica Acta, vol. 1639, no. 3, pp. 203–212, 2003.
[19]
E. ？zk？k, M. Aydin, E. Babalik, Z. Ozbek, N. Ince, and I. Kara, “Combined impact of matrix metalloproteinase-3 and paraoxonase 1 55/192 gene variants on coronary artery disease in Turkish patients,” Medical Science Monitor, vol. 14, no. 10, pp. CR536–CR542, 2008.
[20]
M. Barbieri, M. Bonafè, R. Marfella et al., “LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 1, pp. 222–225, 2002.
[21]
N. Martinelli, D. Girelli, O. Olivieri et al., “Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease,” Clinical and Experimental Medicine, vol. 5, no. 1, pp. 20–30, 2005.
[22]
R. Malin, O. J？rvinen, T. Sisto, T. Koivula, and T. Lehtim？ki, “Paraoxonase producing PON1 gene M/L55 polymorphism is related to autopsy-verified artery-wall atherosclerosis,” Atherosclerosis, vol. 157, no. 2, pp. 301–307, 2001.
[23]
S. Campo, M. A. Sardo, G. Trimarchi et al., “The paraoxonase promoter polymorphism (-107)T > C is not associated with carotid intima-media thickness in Sicilian hypercholesterolemic patients,” Clinical Biochemistry, vol. 37, no. 5, pp. 388–394, 2004.
