Main Article Content
Nitric oxide is one of the important modulators of arterial tone. It is still unclear whether arterial stiffness depends upon NOS3 gene polymorphism in intron 4. The aim of this observational study was to test an association of central hemodynamic and arterial distensibility with VNTR 4b/a NOS3 gene polymorphism determined by PCR, in Caucasian population.
The routinely ascertained tonometry data were studied by pulse wave analysis using SphygmoCor device in 60 healthy Russian miners (27 women) aged 27–65 years and residing in middle Kola Peninsula (68 degrees N).
Paired comparisons showed that male BB homozygotes had lower values of augmentation pressure (p=.005), and higher brachial-to-aortic pulse pressure amplification (p=.002) than A allele carriers (AB and AA genotypes). These associations remain significant after adjusting for age, heart rate, and systolic blood pressure in multiple regression analysis. Female AB carriers had higher aortic systolic blood pressure (p=.046) and lower subendocardial viability ratio (p=.049) compared to homozygous BB subsample.
Individuals carrying A allele thus have stiffer conduit arteries and seem to be at higher risk for cardiovascular diseases.
Vecoli C. Endothelial nitric oxide synthase gene polymorphisms in cardiovascular disease. Vitam Horm. 2014;96:387-406.
Zeng Z, Li L, Zhang Z, Li Y, Wei Z, Huang K, He L, Shi Y. A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy. Hum Genet. 2010;127:373-81. DOI.org/10.1007/s00439-009-0783-x
Liu D, Jiang Z, Dai L, Zhang X, Yan C, Han Y. Association between the -786T>C 1 polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: A systematic review and meta-analysis. Gene. 2014;545(1):175-83.
Rutherford S, Johnson MP, Curtain RP, Griffiths LR. Chromosome 17 and the inducible nitric oxide synthase gene in human essential hypertension. Hum Genetics. 2001;109(4):408–15.
Berger K, Stögbauer F, Stoll M, Wellmann J, Huge A, Cheng S, Kessler C, John U, Assmann G, Ringelstein EB. The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case–control studies. Hum. Genetics. 2007;121(2):169–78.
Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Sumida H, Sugiyama S, Kugiyama K, Ogawa H, Ogawa Y, Saito Y, et al K. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum. Genetics. 1998;103(1): 65-9.
Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: A HuGE review. Am J Epidemiol. 2006;164:921-35.
Kong XZ, Zhang ZY, Wei LH, Li R, Yu J. The endothelial nitric oxide synthase gene T-786C polymorphism increases myocardial infarction risk: A meta-analysis. Med Sci Monit. 2017;23:759-66.
Jaramillo PC, Lanas C, Lanas F, Salazar LA. Polymorphisms of the NOS3 gene in Southern Chilean subjects with coronary artery disease and controls. Clin Chim Acta. 2010;411:258-62.
Afanasiev SA, Muslimova EF, Rebrova TY, Sergienko TN, Repin AN. Association of I/D and T-786C polymorphisms of ACE and NOS3 genes with features of the course of ischemic heart disease and diabetes mellitus type 2. Kardiologiia. In Russian. 2016;56(9):5–10.
Lacolley P, Gautier S, Poirier O, Pannier B, Cambien F, Benetos A. Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects. J Hypertens. 1998;16:31-5.
Pawlik A, Błaszczyk H, Rać M, Maciejewska-Skrendo A, Safranow K, Violetta Dziedziejko V. NOS3 gene rs1799983 and rs2070744 polymorphisms in patients with unstable angina. J Vasc Res. 2020;57(3): 136-42.
Vasilakou M, Votteas V, Kasparian C, Pantazopoulos N, Dedoussis G, Deltas C, et al. Lack of association between endothelial nitric oxide synthase gene polymorphisms and risk of premature coronary artery disease in the Greek population. Acta Cardiol. 2008;63(5):609–14.
Arda E, Ay A, Akdere H, Akdeniz E. The association of Intron 4 VNTR and Glu298Asp polymorphisms of the nitric oxide synthetase 3 gene and vasculogenic erectile dysfunction in Turkish men. Syst Biol Reprod Med. 2019;65(5):383-89.
Rao S, Austin H, Davidoff MN, Zafari AM. Endothelial nitric oxide synthase intron 4 polymorphism is a marker for coronary artery disease in African-American and Caucasian men. Ethn Dis. 2005;15:191-7.
Yang Y, Du K, Liu Z, Lu X. Endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphisms and coronary artery disease: evidence from a meta-analysis. Int J Mol Sci. 2014;15:7987-8003.
Gamil S, Erdmann J, Abdalrahman IB, Mohamed AO. Association of NOS3 gene polymorphisms with essential hypertension in Sudanese patients: a case control study. BMC Med Genetics. 2017;18:128.
Joshaghani HR, Salehi A, Samadian E, Gharaei R, Ahmadi AR. Association between NOS3 G894T, T786C and 4a/4b variants and coronary artery diseases in Iranian population. Iran J Public Health. 2018;47:1891-8.
Mamoulakis D, Bitsori M, Galanakis E, Vazgiorakis E, Panierakis C, Goulielmos GN. Intron 4 polymorphism of the endothelial nitric oxide synthase eNOS gene and early microangiopathy in type 1 diabetes. Int J Immunogenet. 2009;36(3): 153–7.
Mulerova TA, Rubtsova EV, Kuz'mina AA, Tatarnikova NP, Maximov VN, Voevoda MI, Ogarkov MU. Ser49Gly polymorphic markers associations of ADRB1 gene and 4a/4b eNOS gene with hypertension and ischemic heart disease among the population of mountain Shoria natives. Systemic Hypertension. In Russian. 2015; 12(2):38-42.
Bilsborough W, Green DJ, Mamotte CD, van Bockxmeer FM, O'Driscoll GJ, Taylor RR. Endothelial nitric oxide synthase gene polymorphism, homocystein, cholesterol and vascular endothelial function. Atherosclerosis. 2003;169:131-8.
Dell'Omo G, Penno G, Pucci L, Fotino C, Lucchesi D, Del Prato S, Pendrinelli R. Lack of association between endothelial nitric oxide synthase gene polymorphisms, microalbuminuria and endothelial dysfunction in hypertensive men. J Hypertens. 2007;25:1389–95.
Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Li S, Boerwinkle E, Berenson GS. Nitric oxide synthase gene polymorphism (G894T) influences arterial stiffness in adults: the Bogalusa Heart Study. Am J Hypertens. 2004; 17(7):553-9.
Lacolley P, Challande P, Osborne-Pellegrin M, Regnault V. Genetics and pathophysiology of arterial stiffness. Cardiovasc Res. 2009;81:637–648.
Lacolley P, Regnault V, Segers P, Laurent S. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease. Physiol Rev. 2017;97:1555-617.
Mitchell GF, Guo CY, Kathiresan S, Vasan RS, Larson MG, Vita JA, Keyes MJ, Vyas M, Newton-Cheh C, Musone SL et al. Vascular stiffness and genetic variation at the endothelial nitric oxide synthase locus: the Framingham Heart Study. Hypertension. 2007;49:1285-90.
Zineh I, Beitelshees AL, Haller MJ. NOS3 polymorphisms are associated with arterial stiffness in children with type I diabetes. Diabetes Care. 2007;30:689-93.
Lambrinoudaki I, Chatzivasileiou P, Stergiotis S, Armeni E, Rizos D, Kaparos G, Augoulea A, Alexandrou A, Georgiopoulos G, Laina A, Stamatelopoulos K. Subclinical atherosclerosis and vascular stiffness in premenopausal women: association with NOS3 and CYBA polymorphisms. Heart Vessels. 2018;33:1434-44.
Mayer O, Jr., Filipovský J, Pešta M, Cifková R, Dolejšova M, Šimon J. The interaction of endothelial nitric oxide synthase polymorphism and current smoking in terms of increased arterial stiffness. Physiol Res. 2010;59:529–36.
Melnikov VN, Suvorova IYu, Belisheva NK. Central hemodynamics and arterial stiffness in adult humans depend on the conditions of early development in the northern Kola Peninsula. Hum. Physiol. 2016;42(2):150–55.
Melnikov VN, Baranov VI, Suvorova IYu, Krivoschekov SG. Associations of Del 301-303 alpha2B-adrenoceptor gene polymorphism with central hemodynamic parameters in the northern Russian population. Physiol Genomics. 2018;50(2): 100-1. DOI:10.1152/physiolgenomics.00071.2017. Epub 2017 Dec 8.PMID: 29212846
Butlin M, Qasem A. Large artery stiffness assessment using SphygmoCor technology. Pulse. 2016;4:180-92.
Hashimoto J, Ito S. Pulse pressure amplification, arterial stiffness, and peripheral wave reflection determine pulsative flow waveform of the femoral artery. Hypertension. 2010;56:926-33.
Vedam H, Phillips C, Wang D, Barnes DJ, Hedner JA, Unger G, Grunstein RR. Short-term hypoxia reduces arterial stiffness in healthy men Eur J Appl Physiol. 2009;105:19-25.
Katkam SK, Indumathi B, Tasneem FSD, Rajasekhar L, Kutala VK. Impact of eNOS 27-bp VNTR (4b/a) gene polymorphism with the risk of Systemic Lupus Erythematosus in south Indian subjects. Gene. 2018;658:105-12.
Anlıaçık SÖ, Tokgöz S, Zamani AG, Yıldırım MS, İyisoy MS. Investigation of the relationship between ischemic stroke and endothelial nitric oxide synthase gene polymorphisms [G894T, intron 4 VNTR and T786C]. Turk J Med Sci. 2019;49(2): 589-94.
Patkar S, Charita BH, Ramesh C, Padma T. High risk of essential hypertension in males with intron 4 VNTR polymorphism of eNOS gene. Indian J Hum Genet. 2009;15(2):49–53.
Lamnissou K, Zirogiannis P, Trygonis S, Demetriou K, Pierides A, Koptides M, Deltas CC. Evidence for association of endothelial cell nitric oxide synthase gene polymorphism with earlier progression to end-stage renal disease in a cohort of Hellens from Greece and Cyprus. Genetic Testing. 2004;8:319–24.
Mamoulakis D, Bitsori M, Galanakis E, Vazgiourakis V, Panierakis C, Goulielmos GN. Intron 4 polymorphism of the endothelial nitric oxide synthase eNOS gene and early microangiopathy in type 1 diabetes. Int J Immunogenet. 2009;36(3): 153-7. DOI:10.1111/j.1744-313X.2009.00839.x.
Foulds HJA, Bredin SSD, Warburton DER. The vascular health status of a population of adult Canadian Indigenous peoples from British Columbia. J. Hum. Hypertens. 2016;30(4):278–84.
Foulds HJ, Bredin SS, Warburton DE. Ethnic differences in vascular function and factors contributing to blood pressure. Can. J. Public Health. 2018;109(3):316–26.
Bjerregaard P, Dewailly E, Young TK, Blanchet C, Hegele RA, Ebbesson SE, et al. Blood pressure among the Inuit (Eskimo) populations in the Arctic. Scand. J. Public Health. 2003;31(2):92–9.
Foulds HJ, Warburton DE. The blood pressure and hypertension experience among North American Indigenous populations. J. Hypertens. 2014;32(4): 724–34.