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Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease

Molecular Biology Reports volume 40, pages 3065–3071 (2013)Cite this article

Abstract

Genetic polymorphism of the endothelial nitric oxide synthase (eNOS) affects the pathogenesis of atherosclerosis and associated with premature coronary artery disease (PCAD). We aimed to explore the association between Glu298Asp polymorphism of the eNOS gene and premature CAD in Egyptians, and the possible interaction between this polymorphism and other risk factors. The study population consisted of 116 patients with PCAD, and 119 controls. Glu298Asp polymorphism (rs1799983) of the eNOS gene was analyzed by polymerase chain reaction (PCR). We found that the TT genotype of the eNOS gene increased the risk of PCAD by 2.6. Hypertension, diabetes, smoking, total cholesterol, triglycerides, LDLc, HDLc and TT genotype of the eNOS gene were independent risk factors for the development of PCAD. We conclude that, the TT genotype of Glu298Asp polymorphism of eNOS gene is an independent risk factor of PCAD in Egyptians. The association of smoking, obesity, dyslipidemia and/or metabolic syndrome with the TT genotype increased the risk of the development of PCAD.

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References

  1. Isordia-Salas I, Leaños-Miranda A, Borrayo-Sánchez G (2010) The Glu298ASP polymorphism of the endothelial nitric oxide synthase gene is associated with premature ST elevation myocardial infarction in Mexican population. Clin Chim Acta 411:553–557

    PubMed  Article  CAS  Google Scholar 

  2. Szolnoki Z (2009) Evaluation of common unfavourable genetic variants in cerebrovascular diseases: recommendation for supportive genetic examinations and methodological approaches for common genetic variants. Curr Med Chem 16:3168–3173

    PubMed  Article  CAS  Google Scholar 

  3. Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM (1993) Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem 268:17478–17488

    PubMed  CAS  Google Scholar 

  4. Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012

    PubMed  Article  CAS  Google Scholar 

  5. Wang XL, Wang J (2000) Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 70:241–251

    PubMed  Article  CAS  Google Scholar 

  6. Hingorani AD (2003) Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep 5:19–25

    PubMed  Article  Google Scholar 

  7. Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanabe Y, Yoshii Y, Kihara M, Kimura K, Ishii M, Umemura S (1998) Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 32:521–526

    PubMed  Article  CAS  Google Scholar 

  8. Casas JP, Bautista LE, Humphries SE, Hingorani AD (2004) Endothelial nitric oxide synthase genotype and heart disease. Meta-analysis of 26 studies involving 23038 subjects. Circulation 109:1359–1365

    PubMed  Article  CAS  Google Scholar 

  9. Cam SF, Sekuri C, Tengiz I, Ercan E, Sagcan A, Akinm M, Berdeli A (2005) The G894T polymorphism on endothelial nitric oxide synthase gene is associated with premature coronary artery disease in a Turkish population. Throm Res 116:287–292

    Article  CAS  Google Scholar 

  10. Abd El-Aziz TA, Hussein YM, Mohamed RH, Shalaby SM (2012) Renin–angiotensin system genes polymorphism in Egyptians with premature coronary artery disease. Gene 498:270–275

    PubMed  Article  CAS  Google Scholar 

  11. Executive Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497

    Google Scholar 

  12. Frieldewald WT, Levy RS, Fridricken DS (1972) Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1:499–502

    Google Scholar 

  13. Assman SF, Hosmer DW, Lemeshow S, Mundt KA (1996) Confidence intervals for measures of interaction. Epidemiology 7:286–290

    Article  Google Scholar 

  14. Roncaglioni MC, Santoro L, D’Avanzo B, Negri E, Nobili A, Ledda A, Pietropaolo F, Franzosi MG, LaVecchia C, Feruglio GA, Maseri A (1992) Role of family history in patients with myocardial infarction: an Italian case-control study. GISSIEFRIM Investigators. Circulation 85:2065–2072

    PubMed  Article  CAS  Google Scholar 

  15. Berdeli A, Sekuri C, Cam FS, Ercan E, Sagcan A, Tengiz I, Eser E, Akın M (2005) Association between the eNOS (Glu298Asp) and the RAS genes polymorphisms and premature coronary artery disease in a Turkish population. Clin Chim Acta 351:87–94

    PubMed  Article  CAS  Google Scholar 

  16. Gardemann A, Lohre J, Cayci S, Katz N, Tillmanns H, Haberbosch W (2002) The T allele of the missense Glu298Asp endothelial nitric oxide synthase gene polymorphism is associated with coronary heart disease in younger individuals with high atherosclerotic risk profile. Atherosclerosis 160:167–175

    PubMed  Article  CAS  Google Scholar 

  17. Aras O, Hanson NQ, Bakanay SM, Tsai MY, Gulec S (2002) Endothelial nitric oxide gene polymorphism (Glu298Asp) is not associated with coronary artery disease in Turkish population. Thromb Haemost 87:347–349

    PubMed  CAS  Google Scholar 

  18. Nassar BA, Bevin LD, Johnstone DE, O’Neill BJ, Bata IR, Kirkland SA, Title LM (2001) Relationship of the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and early-onset coronary artery disease. Am Heart J 142(4):586–589

    PubMed  Article  CAS  Google Scholar 

  19. Karvonen J, Kauma H, Kervinen K, Rantala M, Ikäheimo M, Päivänsalo M, Savolainen MJ, Kesäniemi YA (2002) Endothelial nitric oxide synthase gene Glu298Asp polymorphism and blood pressure, left ventricular mass and carotid artery atherosclerosis in a population-based cohort. J Intern Med 251(2):102–110

    PubMed  Article  CAS  Google Scholar 

  20. Guo X, Cheng S, Taylor KD, Cui J, Hughes R, Quinones MJ, Bulnes-Enriquez I, De la Rosa R, Aurea G, Yang H, Hsueh W, Rotter JI (2005) Hypertension genes are genetic markers for insulin sensitivity and resistance. Hypertension 45:799–803

    PubMed  Article  CAS  Google Scholar 

  21. Shimasaki Y, Yasue H, Yoshimura M, Nakayama M, Kugiyama K, Ogawa H (1998) Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 31:1506–1510

    PubMed  Article  CAS  Google Scholar 

  22. Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Ogawa H, Kugiyama K, Saito Y, Miyamoto Y, Ogawa Y, Kaneshige T, Hiramatsu H, Yoshioka T, Kamitani S, Teraoka H, Nakao K (2000) Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T786C and missense Glu298Asp variants. J Investig Med 48:367–374

    PubMed  CAS  Google Scholar 

  23. Colombo MG, Andreassi MG, Paradossi U, Botto N, Manfredi S, Masetti S, Rossi G, Clerico A, Biagini A (2002) Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298 → Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart 87:525–528

    PubMed  Article  CAS  Google Scholar 

  24. Antoniades C, Tousoulis D, Vasiliadou C, Pitsavos C, Chrysochoou C, Panagiotakos D, Tentolouris C, Marinou K, Koumallos N, Stefanadis C (2005) Genetic polymorphism on endothelial nitric oxide synthase affects endothelialn activation and inflammatory response during the acute phase of myocardial infarction. J Am Coll Cardiol 46:1101–1109

    PubMed  Article  CAS  Google Scholar 

  25. Poirier O, Mao C, Mallet C, Nicaud V, Herrmann SM, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L (1999) Polymorphisms of the endothelial nitric oxide synthase gene—no consistent association with myocardial infarction in the ECTIM study. Eur J Clin Invest 29:284–290

    PubMed  Article  CAS  Google Scholar 

  26. Wang CL, Hsu LA, Ko YS, Ko YL, Lee YH (2001) Lack of association between the Glu298Asp variant of the endothelial nitric oxide synthase gene and the risk of coronary artery disease among Taiwanese. J Form Med Assoc 100:736–740

    CAS  Google Scholar 

  27. Granath B, Taylor RR, van Bockxmeer FM, Mamotte CD (2001) Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population. J Cardiovasc Risk 8:235–241

    PubMed  Article  CAS  Google Scholar 

  28. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 347:1916–1923

    PubMed  Article  CAS  Google Scholar 

  29. Fricker R, Hesse C, Weiss J, Tayrouz Y, Hoffmann MM, Unnebrink K, Mansmann U, Haefeli WE (2004) Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation. Br J Clin Pharmacol 58:169–177

    PubMed  Article  CAS  Google Scholar 

  30. Rossi GP, Taddei S, Virdis A, Cavallin M, Ghiadoni L, Favilla S, Versari D, Sudano I, Pessina AC, Salvetti A (2003) The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 41:938–945

    PubMed  Article  CAS  Google Scholar 

  31. Paradossi U, Ciofini E, Clerico A, Botto N, Biagini A, Colombo MG (2004) Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298 → Asp and T–786 → C polymorphisms. Stroke 35(6):1305–1309

    PubMed  Article  Google Scholar 

  32. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O’Shaughnessy KM, Brown MJ (1999) A common variant of the endothelial nitric oxide synthase (Glu298-Asp) is a major risk factor for coronary artery disease in the UK. Circulation 100:1515–1520

    PubMed  Article  CAS  Google Scholar 

  33. Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126

    PubMed  Article  CAS  Google Scholar 

  34. De Caterina R (2000) Endothelial dysfunctions: common denominators in vascular disease. Curr Opin Lipidol 11:9–23

    PubMed  Article  Google Scholar 

  35. Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, Valsecchi G, Lucotti P, Pozza G, Bernardinelli L, Casari G, Piatti P (2003) Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 52(5):1270–1275

    PubMed  Article  CAS  Google Scholar 

  36. Hayden MR, Tyagi SC (2003) Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stres. Cardiovasc Diabetol. 2:2

    PubMed  Article  Google Scholar 

  37. Bayoglu B, Ersoz M, Cagatay P, Ciftci C, Duman BS (2008) Lack of association between endothelial nitric oxide synthase Glu298Asp variation, visceral obesity and insulin related phenotypes in Turkish type 2 diabetic patients. Acta Medica Academica 37:91–98

    Google Scholar 

  38. Ukkola O, Erkkila PH, Savolainen MJ, Kesaniemi YA (2001) Lack of association between polymorphism of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Int Med. 249(5):451–459

    Article  CAS  Google Scholar 

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Acknowledgments

This study was funded with the support of academic research in Zagazig University Projects, Post Graduate & Research Affairs, Zagazig University, Zagazig, Egypt.

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Affiliations

  1. Cardiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    T. A. Abdel-Aziz

  2. Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt

    R. H. Mohamed

Authors
  1. T. A. Abdel-Aziz
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  2. R. H. Mohamed
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Correspondence to R. H. Mohamed.

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Abdel-Aziz, T.A., Mohamed, R.H. Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease. Mol Biol Rep 40, 3065–3071 (2013). https://doi.org/10.1007/s11033-012-2380-7

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  • DOI: https://doi.org/10.1007/s11033-012-2380-7

Keywords

  • eNOS
  • Genetic polymorphism
  • Premature CAD