Association of Variants of 786T>C (rs2070744) Polymorphism of the NOS3 Gene with Age-Dependent Electrophysiological Disorders in Myocardium

The aim of the study was to examine associations of ECG signal micro-alternations values with various variants of the 786T>C (rs2070744) polymorphism of the NOS3 gene in cohorts of mature and elderly male Northerners.

Materials and Methods. One hundred forty male residents of the Magadan Region (Russia) aged 25–80 were included in the study. All the examinees were classified into mature and elderly. Men of different ages were divided into two groups based on the presence/absence of the NOS3*C allele in their genotypes: group 1 consisted of homozygous men (TT genotype); group 2 — of heterozygous and homozygous carriers of the NOS3*C allele (TC+CC genotypes). Genetic SNP testing and methods for assessing the characteristics of cardiac variance mapping were used.

Results. The study revealed age-associated impairment of dispersion characteristics of ECG signal, the “Myocardium” and “Rhythm” indices, as well as myocardial electrophysiological disorders, which were more characteristic of the elderly men who were carriers of the minor NOS3*C allele (genotypes TC+CC). This was accompanied by a synchronous increase in the “rigidity” of the matrix of ECG dispersion mapping indicators. The two-factor dispersion analysis showed that the 786T>C (rs2070744) polymorphism of the NOS3 gene significantly influenced the ventricular hypertrophy (G9) at simultaneous cumulative impact with the age factor: the “Age” factor on the “Myocardium” index, right and left ventricular repolarization (G5, G6), and their depolarization symmetry (G7).

Conclusion. The results indicate that monitoring studies of the main characteristics of ECG dispersion mapping parameters in addition to the evaluation of 786T>C (rs2070744) polymorphism of the NOS3 gene must be given emphasis since it is crucial for the formation of personalized and preventive medicine. It has been established that the presence of the minor allele NOS3*C of the polymorphism 786T>C (rs2070744) of the NOS3 locus can be considered as an additional risk factor for age-associated electrophysiological disorders of the myocardium.

1. Ivanov G.G., Sula A.S. Dispersionnoe EKG-kartirovanie: teoreticheskie osnovy i klinicheskaya praktika [Dispersion ECG mapping: theoretical foundations and clinical practice]. Moscow: Tekhnosfera; 2009.
2. Esina E.Y., Zuikova A.A., Dobrynina I.S., Lyutov V.V., Tsygan V.N. ECG dispersion mapping in preclinical diagnosis of cardiovascular diseases. Sovremennye tehnologii v medicine 2021; 12(5): 87–92, https://doi.org/10.17691/stm2020.12.5.10.
3. Maslennikova O.M., Ardashev V.N., Novikov E.M., Stepanov M.M., Stebletsov S.V., Kirillova T.B., Tarabarina N.B., Perets E.M., Fursov A.N. Assessment of the pre-test probability of ischemic heart disease according to the data of dispersion mapping of an electrocardiogram and analysis of heart rate variability. Kliniceskaa medicina 2022; 100(4–5): 178–184, https://doi.org/10.30629/0023-2149-2022-100-4-5-178-184.
4. McIntyre M., Dominiczak A.F. Nitric oxide and cardiovascular disease. Postgrad Med J 1997; 73(864): 630–634, https://doi.org/10.1136/pgmj.73.864.630.
5. Tran N., Garcia T., Aniqa M., Ali S., Ally A., Nauli S.M. Endothelial nitric oxide synthase (eNOS) and the cardiovascular system: in physiology and in disease states. Am J Biomed Sci Res 2022; 15(2): 153–177.
6. Niu W., Qi Y. An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension. PLoS One 2011; 6(9): e24266, https://doi.org/10.1371/journal.pone.0024266.
7. Dai B., Liu T., Zhang B., Zhang X., Wang Z. The polymorphism for endothelial nitric oxide synthase gene, the level of nitric oxide and the risk for pre-eclampsia: a meta-analysis. Gene 2013; 519(1): 187–193, https://doi.org/10.1016/j.gene.2013.01.004.
8. Shoukry A., Shalaby S.M., Abdelazim S., Abdelazim M., Ramadan A., Ismail M.I., Fouad M. Endothelial nitric oxide synthase gene polymorphisms and the risk of diabetic nephropathy in type 2 diabetes mellitus. Genet Test Mol Biomarkers 2012; 16(6): 574–579, https://doi.org/10.1089/gtmb.2011.0218.
9. Eröz R., Bahadir A., Dikici S., Tasdemir S. Association of endothelial nitric oxide synthase gene polymorphisms (894G/T, -786T/C, G10T) and clinical findings in patients with migraine. Neuromolecular Med 2014; 16(3): 587–593, https://doi.org/10.1007/s12017-014-8311-0.
10. Hendrix P., Foreman P.M., Harrigan M.R., Fisher W.S. Rd, Vyas N.A., Lipsky R.H., Lin M., Walters B.C., Tubbs R.S., Shoja M.M., Pittet J.F., Mathru M., Griessenauer C.J. The role of endothelial nitric oxide synthase -786 T/C polymorphism in cardiac instability following aneurysmal subarachnoid hemorrhage. Nitric Oxide 2017; 71: 52–56, https://doi.org/10.1016/j.niox.2017.10.008.
11. Hendrix P., Foreman P.M., Harrigan M.R., Fisher W.S. 3rd, Vyas N.A., Lipsky R.H., Lin M., Walters B.C., Tubbs R.S., Shoja M.M., Pittet J.F., Mathru M., Griessenauer C.J. Endothelial nitric oxide synthase polymorphism is associated with delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. World Neurosurg 2017; 101: 514–519, https://doi.org/10.1016/j.wneu.2017.02.062.
12. Balligand J.L., Kobzik L., Han X., Kaye D.M., Belhassen L., O’Hara D.S., Kelly R.A., Smith T.W., Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J Biol Chem 1995; 270(24): 14582–14586, https://doi.org/10.1074/jbc.270.24.14582.
13. Petroff M.G., Kim S.H., Pepe S., Dessy C., Marbán E., Balligand J.L., Sollott S.J. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 2001; 3(10): 867–873, https://doi.org/10.1038/ncb1001-867.
14. Wallerath T., Gath I., Aulitzky W.E., Pollock J.S., Kleinert H., Förstermann U. Identification of the NO synthase isoforms expressed in human neutrophil granulocytes, megakaryocytes and platelets. Thromb Haemost 1997; 77(1): 163–167.
15. Kleinbongard P., Schulz R., Rassaf T., Lauer T., Dejam A., Jax T., Kumara I., Gharini P., Kabanova S., Ozüyaman B., Schnürch H.G., Gödecke A., Weber A.A., Robenek M., Robenek H., Bloch W., Rösen P., Kelm M. Red blood cells express a functional endothelial nitric oxide synthase. Blood 2006; 107(7): 2943–2951, https://doi.org/10.1182/blood-2005-10-3992.
16. Bebyakova N.A., Levitsky S.N., Pervukhina O.A. Polymorphism genes of the renin-angiotensin system in residents of the European North. Sovremennyye problemy nauki i obrazovaniya 2019; 3, https://science-education.ru/ru/article/view?id=28793.
17. Danilova I.A. Interregional inequality in life expectancy in Russia and its components by age and causes of death. Social Aspects of Population Health 2017; 5(57): 3, https://doi.org/10.21045/2071-5021-2017-57-5-3.
18. Revich B.А., Khar’kova Т.L., Kvasha Е.А. Mortality among adults in the Arctic macro-region: dynamics, structure and features. Health Risk Analysis 2023; (1): 13–26, https://doi.org/10.21668/health.risk/2023.1.02.eng.
19. Programmnoe obespechenie dlya skriningovykh issledovaniy serdtsa “KardioVizor-06s” (rukovodstvo pol’zovatelya) [KardioVizor-06s software for cardiac screening (user manual)]. Moscow; 2004.
20. Solonin Iu.G., Markov A.L., Boiko E.R., Lysenkov I.I., Efimov A.V. Specific features of electrocardiogram dispersion mapping readings in apparently health dwellers of the North. Profilakticheskaya meditsina 2013; 16(5): 48–52.
21. Ivanov G.G., Bulanova N.A., Nikolaeva M.B., Schelykalina S.P., Nikolaev D.V., Halabi G. Myocardial micro-alternation index: influence of age, gender and pre valence of normal values in screening of the population. Medical News of the North Caucasus 2018; 13(4): 589–593, https://doi.org/10.14300/mnnc.2018.13111.
22. Poskotinova L.V., Zenchenko T.A., Medvedeva A.A., Ovsyankina M.A. The relation of heart rate variability and a dispersive electrocardiogram mapping indicators in human during fixed rate breathing test. Annals of the Russian Academy of Medical Sciences 2012; 67(7): 44–49, https://doi.org/10.15690/vramn.v67i7.340.

Averyanova I.V., Loskutova A.N., Bezmenova I.N. Association of Variants of 786T>C (rs2070744) Polymorphism of the NOS3 Gene with Age-Dependent Electrophysiological Disorders in Myocardium. Sovremennye tehnologii v medicine 2025; 17(5): 87, https://doi.org/10.17691/stm2025.17.5.06