Association between NOS3 G894T, T-786C and 4a/4b Variants and Coronary Artery Diseases in Iranian Population
Abstract
Background: Endothelial nitric oxide synthase, encoded by NOS3, produces an atheroprotective metabolite. The G894T, T-786C and 4a/4b variants of this gene associated with increased risk for coronary artery diseases (CAD) have been evaluated in different populations worldwide, and inconsistent results have been obtained. We investigated the association between these three polymorphisms and presence of CAD in Iranian individuals.
Methods: Overall, 234 people including angiography-positive patients from Amir-Almomenin Hospital (Heart Center), Kordkoy City, Golestan Province, northern Iran in 2016, angiography-negative subjects and healthy individuals from north of Iran were genotyped for the G894T and T−786C variations by PCR-RFLP, and 4a/4b VNTR only by PCR.
Results: The genotype distribution and allelic frequencies for the three variants tested were not dramatically different between CAD and control subjects and also between CAD patients and people with pains and symptoms very similar to CAD but no stenosis (P>0.05). Moreover, the odds ratio for CAD related to the G894T (OR=1.09, 95% CI=(0.60-2.00), T-786C (OR=1.04, 95% CI=(0.57-1.89) and 4a/4b (OR=1.75, 95% CI=(0.92-3.32) variants did not show statistical significance. Similarly, the odds ratio for stenosis confirmed by angiography related to the 894T (OR=1.03, 95% CI= (0.61-1.74), -786C (OR=0.90, 95% CI=(0.54-1.50) and 4b (OR=1.64, 95% CI=(0.92 -2.93) alleles were not significant.
Conclusion: G894T, T-786C and 4a/4b variants were not associated with risk for CAD and occurrence of angiography-assessed stenosis in Northern Iranian population (P>0.05). These alleles might be population-specific and not to be associated with their corresponding gene pool. However, further analysis is required to clarify other CAD-correlated markers in our community.
1. Lander ES(1996). The new genomics: global views of biology. Science, 274(5287): 536-9.
2. Risch N, Merikangas K(1996). The future of genetic studies of complex human diseases. Science, 273(5281): 1516-7.
3. Colombo MG, Paradossi U, Andreassi MG, Botto N, Manfredi S, Masetti S, et al(2003). Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem, 49:389-395.
4. Hingorani AD (2001). Polymorphisms in endothelial nitric oxide synthase and atherogenesis: John French Lecture 2000. Atherosclerosis, 154(3): 521-7.
5. Kim IJ, Bae J, Lim SW et al (2007). Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease. Thromb Res, 119: 579-85.
6. Marsden PA, Heng HH, Scherer SW et al (1993). Structure and Chromosomal Localization of the Human Constitutive Endothelial Nitric-Oxide Synthase Gene. J Biol Chem, 268(23): 17478-17488.
7. Berdeli A, Sekuri C, Sirri Cam F et al (2005). Association between the eNOS (Glu298Asp) and the RAS genes polymorphisms and premature coronary artery disease in a Turkish population. Clin Chim Acta, 351(1-2):87-94.
8. Liu D, Jiang Z, Dai L et al (2014). Association between the-786T > C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: A systematic review and meta-analysis. Gene, 545(1): 175-83.
9. Rai H, Parveen F, Kumar S, Kapoor A, Sinha N (2014). Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review. PLoS One, 9(11): e113363.
10. Yang Y, Du K, Liu Z, Lu X (2014). Endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphisms and coronary artery disease: evidence from a meta-analysis. Int J Mol Sci, 15(5): 7987-8003.
11. Lahiri DK, Schnabel B (1993). DNA isolation by a rapid method from human blood samples: effects of MgCl2, EDTA, storage time, and temperature on DNA yield and quality. Biochem Genet, 31(7-8): 321-8.
12. Andrikopoulos GK, Grammatopoulos DK, Tzeis SE et al. (2008). Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction. BMC Med Genet, 9: 43.
13. Colomba D, Duro G, Corrao S et al (2008). Endothelial nitric oxide synthase gene polymorphisms and cardiovascular damage in hypertensive subjects: an Italian case-control study. Immun Ageing, 5: 4.
14. Nath SD, He X, Voruganti VS, Blangero J et al (2009). The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans. Mol Cell Biochem, 331(1-2): 201-5.
15. Mehrtashfar Sh, Ebrahimi A (2014). Association of the eNOS 894 G > T gene polymorphisms and risk of coronary artery disease in Iranian population. Int J Basic Biosci, 2:27-30.
16. Safarinejad MR, Khoshdel A, Shekarchi B, Taghva A, Safarinejad S (2011). Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects. BJU Int, 107(12): 1994-2001.
17. Salimi S, Firoozrai M, Zand H et al (2010). Endothelial nitric oxide synthase gene Glu298Asp polymorphism in patients with coronary artery disease. Ann Saudi Med, 30(1): 33-7.
18. Rahimi Z, Nourozi-Rad R (2012). Association of endothelial nitric oxide synthase gene variant (G894T) with coronary artery disease in Western Iran. Angiology, 63(2): 131-7.
19. Hingorani AD, Liang CF, Fatibene J et al (1999). A common variant of the endothelial nitric oxide synthase (Glu(298)-> Asp) is a major risk factor for coronary artery disease in the UK. Circulation, 100(14): 1515-20.
20. Szabo GV, Kunstar A, Acsady G (2009). Methylentetrahydrofolate reductase and nitric oxide synthase polymorphism in patients with atherosclerosis and diabetes. Pathol Oncol Res, 15:631-7.
21. Lin NT, Lee MJ, Lee RP Hong AI, Chen HI (2008). Analysis of endothelial nitric oxide synthase gene polymorphisms with cardiovascular diseases in eastern Taiwan. Chin J Physiol,51:42-7.
22. Younan H, Razek G, Elkhashab KH, Abdelrasol H, Saad M (2015). Relationship of endothelial nitric oxide synthase gene polymorphism with atherosclerotic coronary and carotid arterial disease in Egyptian Population. The Egyptian Heart Journal, 67: 225-232.
23. Ben Ali M, Messaoudi S, Ezzine H, Mahjoub T (2015). Contribution of eNOS variants to the genetic susceptibility of coronary artery disease in a Tunisian population. Genet Test Mol Biomarkers, 19:203-8.
24. Cai H, Wilcken DEL, Wang XL (1999). The Glu-298 -> Asp (894G -> T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. J Mol Med (Berl), 77: 511-514.
25. Liyou N, Simons L, Friedlander Y et al (1998). Coronary artery disease is not associated with the E298 -> D variant of the constitutive, endothelial nitric oxide synthase gene. Clin Genet, 54:528-529.
26. Jaramillo PC, Lanas C, Lanas F, Salazar LA (2010). Polymorphisms of the NOS3 gene in Southern Chilean subjects with coronary artery disease and controls. Clin Chim Acta, 411:258-262.
27. 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 Haemostasis. 87:347-349.
28. Gluba A1, Banach M, Rysz J, Piotrowski G, Fendler W, Pietrucha T (2009). Is Polymorphism Within eNOS Gene Associated With the Late Onset of Myocardial Infarction? A Pilot Study. Angiology. 60:588-595.
29. Alkharfy KM1, Al-Daghri NM, Al-Attas OS et al (2010). Endothelial Nitric Oxide Synthase Gene Polymorphisms (894G > T and-786T > C) and Risk of Coronary Artery Disease in a Saudi Population. Arch Med Res. 41:134-141.
30. Mathew J1, Narayanan P, Sundaram R et al (2008). Lack of association between Glu(298) asp polymorphism of endothelial nitric oxide synthase (eNOS) gene and coronary artery disease in Tamilian population. Indian Heart J, 60:223-7.
31. Khaki-Khatibi F YAR, Ghojazadeh M, Rahbani-Nobar M (2012). Association between T-786C polymorphism of endothelial nitric oxide synthase gene and level of the vessel dilation factor in patients with coronary artery disease. Molecular Biology Research Communications, 1:1-7.
32. Nakayama M1, Yasue H, Yoshimura M et al (1999). T-786 --> C mutation in the 5 '-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation, 99: 2864-2870.
33. Bae J, Kim IJ, Hong SH et al (2010). Association of endothelial nitric oxide synthase polymorphisms with coronary artery disease in Korean individuals with or without diabetes mellitus. Exp Ther Med, 1:719-724.
34. Sezgin N, Tekin A, Atac FB, Verdi H, Turan Sezgin A (2015). Endothelial nitric oxide synthase genes (intron 4a/b and T786C) polymorphisms in coronary artery disease in North Indian subjects. International Journal of Current Pharmaceutical & Clinical Research, 5:48-51.
35. Abolhalaj M, Amoli MM, Amiri P (2013). eNOS Gene Variant in Patients with Coronary Artery Disease. J Biomark, 403783.
36. Salimi S, Firoozrai M, Nourmohammadi I, Shabani M, Mohebbi A (2006). Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with coronary artery disease in Iran. Indian J Med Res, 124: 683-8.
37. Zarmakhi L, Hashemi M (2012). The analysis of endothelial nitric oxide synthase gene polymorphism in intron 4 with hypertension disease. JPS, 3(1): 2-6.
38. Matyar S, Attila G, Acartürk E, Akpinar O, Inal T (2005). eNOS gene intron 4 a/b VNTR polymorphism is a risk factor for coronary artery disease in Southern Turkey. Clin Chim Acta, 354(1-2): 153-8.
39. Angeline T, Isabel W, Tsongalis GJ (2010). Endothelial nitric oxide gene polymorphisms, nitric oxide production and coronary artery disease risk in a South Indian population. Exp Mol Pathol, 89(3): 205-8.
40. Narne P, Ponnaluri KC, Singh S, Siraj M, Ishaq M (2013). Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus. J Diabetes Complications, 27(3): 255-61.
41. Wang R, Dudley D, Wang XL (2002). Haplotype-specific effects on endothelial NO synthase promoter efficiency - Modifiable by cigarette smoking. Arterioscler Thromb Vasc Biol, 22(5): e1-e4.
42. Miyamoto Y, Saito Y, Nakayama M et al (2000). Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a-786T -> C mutation associated with coronary spastic angina. Hum Mol Genet, 9(18): 2629-37.
43. Hingorani AD (2003). Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep, 5(1):19-25.
44. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000). Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci U S A, 97(6): 2832-5.
45. Valero N, Espina LM, Añez G, Torres E, Mosquera JA (2002). Short report: in-creased level of serum nitric oxide in pa-tients with dengue. Am J Trop Med Hyg, 66(6): 762-4.
2. Risch N, Merikangas K(1996). The future of genetic studies of complex human diseases. Science, 273(5281): 1516-7.
3. Colombo MG, Paradossi U, Andreassi MG, Botto N, Manfredi S, Masetti S, et al(2003). Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem, 49:389-395.
4. Hingorani AD (2001). Polymorphisms in endothelial nitric oxide synthase and atherogenesis: John French Lecture 2000. Atherosclerosis, 154(3): 521-7.
5. Kim IJ, Bae J, Lim SW et al (2007). Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease. Thromb Res, 119: 579-85.
6. Marsden PA, Heng HH, Scherer SW et al (1993). Structure and Chromosomal Localization of the Human Constitutive Endothelial Nitric-Oxide Synthase Gene. J Biol Chem, 268(23): 17478-17488.
7. Berdeli A, Sekuri C, Sirri Cam F et al (2005). Association between the eNOS (Glu298Asp) and the RAS genes polymorphisms and premature coronary artery disease in a Turkish population. Clin Chim Acta, 351(1-2):87-94.
8. Liu D, Jiang Z, Dai L et al (2014). Association between the-786T > C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: A systematic review and meta-analysis. Gene, 545(1): 175-83.
9. Rai H, Parveen F, Kumar S, Kapoor A, Sinha N (2014). Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review. PLoS One, 9(11): e113363.
10. Yang Y, Du K, Liu Z, Lu X (2014). Endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphisms and coronary artery disease: evidence from a meta-analysis. Int J Mol Sci, 15(5): 7987-8003.
11. Lahiri DK, Schnabel B (1993). DNA isolation by a rapid method from human blood samples: effects of MgCl2, EDTA, storage time, and temperature on DNA yield and quality. Biochem Genet, 31(7-8): 321-8.
12. Andrikopoulos GK, Grammatopoulos DK, Tzeis SE et al. (2008). Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction. BMC Med Genet, 9: 43.
13. Colomba D, Duro G, Corrao S et al (2008). Endothelial nitric oxide synthase gene polymorphisms and cardiovascular damage in hypertensive subjects: an Italian case-control study. Immun Ageing, 5: 4.
14. Nath SD, He X, Voruganti VS, Blangero J et al (2009). The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans. Mol Cell Biochem, 331(1-2): 201-5.
15. Mehrtashfar Sh, Ebrahimi A (2014). Association of the eNOS 894 G > T gene polymorphisms and risk of coronary artery disease in Iranian population. Int J Basic Biosci, 2:27-30.
16. Safarinejad MR, Khoshdel A, Shekarchi B, Taghva A, Safarinejad S (2011). Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects. BJU Int, 107(12): 1994-2001.
17. Salimi S, Firoozrai M, Zand H et al (2010). Endothelial nitric oxide synthase gene Glu298Asp polymorphism in patients with coronary artery disease. Ann Saudi Med, 30(1): 33-7.
18. Rahimi Z, Nourozi-Rad R (2012). Association of endothelial nitric oxide synthase gene variant (G894T) with coronary artery disease in Western Iran. Angiology, 63(2): 131-7.
19. Hingorani AD, Liang CF, Fatibene J et al (1999). A common variant of the endothelial nitric oxide synthase (Glu(298)-> Asp) is a major risk factor for coronary artery disease in the UK. Circulation, 100(14): 1515-20.
20. Szabo GV, Kunstar A, Acsady G (2009). Methylentetrahydrofolate reductase and nitric oxide synthase polymorphism in patients with atherosclerosis and diabetes. Pathol Oncol Res, 15:631-7.
21. Lin NT, Lee MJ, Lee RP Hong AI, Chen HI (2008). Analysis of endothelial nitric oxide synthase gene polymorphisms with cardiovascular diseases in eastern Taiwan. Chin J Physiol,51:42-7.
22. Younan H, Razek G, Elkhashab KH, Abdelrasol H, Saad M (2015). Relationship of endothelial nitric oxide synthase gene polymorphism with atherosclerotic coronary and carotid arterial disease in Egyptian Population. The Egyptian Heart Journal, 67: 225-232.
23. Ben Ali M, Messaoudi S, Ezzine H, Mahjoub T (2015). Contribution of eNOS variants to the genetic susceptibility of coronary artery disease in a Tunisian population. Genet Test Mol Biomarkers, 19:203-8.
24. Cai H, Wilcken DEL, Wang XL (1999). The Glu-298 -> Asp (894G -> T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. J Mol Med (Berl), 77: 511-514.
25. Liyou N, Simons L, Friedlander Y et al (1998). Coronary artery disease is not associated with the E298 -> D variant of the constitutive, endothelial nitric oxide synthase gene. Clin Genet, 54:528-529.
26. Jaramillo PC, Lanas C, Lanas F, Salazar LA (2010). Polymorphisms of the NOS3 gene in Southern Chilean subjects with coronary artery disease and controls. Clin Chim Acta, 411:258-262.
27. 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 Haemostasis. 87:347-349.
28. Gluba A1, Banach M, Rysz J, Piotrowski G, Fendler W, Pietrucha T (2009). Is Polymorphism Within eNOS Gene Associated With the Late Onset of Myocardial Infarction? A Pilot Study. Angiology. 60:588-595.
29. Alkharfy KM1, Al-Daghri NM, Al-Attas OS et al (2010). Endothelial Nitric Oxide Synthase Gene Polymorphisms (894G > T and-786T > C) and Risk of Coronary Artery Disease in a Saudi Population. Arch Med Res. 41:134-141.
30. Mathew J1, Narayanan P, Sundaram R et al (2008). Lack of association between Glu(298) asp polymorphism of endothelial nitric oxide synthase (eNOS) gene and coronary artery disease in Tamilian population. Indian Heart J, 60:223-7.
31. Khaki-Khatibi F YAR, Ghojazadeh M, Rahbani-Nobar M (2012). Association between T-786C polymorphism of endothelial nitric oxide synthase gene and level of the vessel dilation factor in patients with coronary artery disease. Molecular Biology Research Communications, 1:1-7.
32. Nakayama M1, Yasue H, Yoshimura M et al (1999). T-786 --> C mutation in the 5 '-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation, 99: 2864-2870.
33. Bae J, Kim IJ, Hong SH et al (2010). Association of endothelial nitric oxide synthase polymorphisms with coronary artery disease in Korean individuals with or without diabetes mellitus. Exp Ther Med, 1:719-724.
34. Sezgin N, Tekin A, Atac FB, Verdi H, Turan Sezgin A (2015). Endothelial nitric oxide synthase genes (intron 4a/b and T786C) polymorphisms in coronary artery disease in North Indian subjects. International Journal of Current Pharmaceutical & Clinical Research, 5:48-51.
35. Abolhalaj M, Amoli MM, Amiri P (2013). eNOS Gene Variant in Patients with Coronary Artery Disease. J Biomark, 403783.
36. Salimi S, Firoozrai M, Nourmohammadi I, Shabani M, Mohebbi A (2006). Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with coronary artery disease in Iran. Indian J Med Res, 124: 683-8.
37. Zarmakhi L, Hashemi M (2012). The analysis of endothelial nitric oxide synthase gene polymorphism in intron 4 with hypertension disease. JPS, 3(1): 2-6.
38. Matyar S, Attila G, Acartürk E, Akpinar O, Inal T (2005). eNOS gene intron 4 a/b VNTR polymorphism is a risk factor for coronary artery disease in Southern Turkey. Clin Chim Acta, 354(1-2): 153-8.
39. Angeline T, Isabel W, Tsongalis GJ (2010). Endothelial nitric oxide gene polymorphisms, nitric oxide production and coronary artery disease risk in a South Indian population. Exp Mol Pathol, 89(3): 205-8.
40. Narne P, Ponnaluri KC, Singh S, Siraj M, Ishaq M (2013). Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus. J Diabetes Complications, 27(3): 255-61.
41. Wang R, Dudley D, Wang XL (2002). Haplotype-specific effects on endothelial NO synthase promoter efficiency - Modifiable by cigarette smoking. Arterioscler Thromb Vasc Biol, 22(5): e1-e4.
42. Miyamoto Y, Saito Y, Nakayama M et al (2000). Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a-786T -> C mutation associated with coronary spastic angina. Hum Mol Genet, 9(18): 2629-37.
43. Hingorani AD (2003). Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep, 5(1):19-25.
44. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000). Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci U S A, 97(6): 2832-5.
45. Valero N, Espina LM, Añez G, Torres E, Mosquera JA (2002). Short report: in-creased level of serum nitric oxide in pa-tients with dengue. Am J Trop Med Hyg, 66(6): 762-4.
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| Issue | Vol 47 No 12 (2018) | |
| Section | Original Article(s) | |
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| Endothelial nitric oxide synthase Coronary artery disease Polymorphism | ||
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How to Cite
1.
JOSHAGHANI HR, SALEHI A, SAMADIAN E, GHARAEI R, AHMADI AR. Association between NOS3 G894T, T-786C and 4a/4b Variants and Coronary Artery Diseases in Iranian Population. Iran J Public Health. 2018;47(12):1891-1898.
