Influence of Guanine Nucleotide-binding Protein Subunit 3 Gene Polymorphism 825 C > T rs5443 on the Development of Diastolic Dysfunction in Late Postmenopausal Women

Introduction. Globally, about 64 million people have been reported to suffer from heart failure, and there with increasing the proportion of heart failure with preserved ejection fraction. GNB3 gene encoding β3 subunit of G-protein may be one of the candidate genes for pharmacogenetic approaches to heart failure management.

Aim: to evaluate the frequency of various polymorphisms of the guanine nucleotide-binding protein subunit 3 gene and their role in the development of diastolic dysfunction.

Methods. A cross-sectional study enrolled 87 late postmenopausal women. All patients underwent transthoracic echocardiography, serum the levels of adrenomedullin, renin, NT-proBNP, total cholesterol, low-density lipoprotein, and glucose were assessed. Polymorphisms of the guanine nucleotide-binding protein subunit 3 gene 825 C > T (rs5443) were evaluated by polymerase chain reaction.

Results. The analysis showed that the C allele presence increased the risks of atherosclerotic changes by predisposing to elevated LDL levels and obesity. Although remodeling analysis showed no statistically significant differences between the three possible genotypes, the C allele predisposes more to dilated changes, and the T allele might increase the likelihood of left ventricular myocardial hypertrophy. There were no statistical differences between groups with and without left ventricular diastolic dysfunction and between patients with different levels of adrenomedullin, renin, NT-proBNP.

Conclusions. The revealed interrelationships of polymorphisms and propensity to cardiovascular conditions can contribute to the development of personalized approach to the diagnosis and treatment of patients with heart failure. Absence of differences in patients with the studied genotypes in relation to the levels of neurohumoral factors may be related to adequate long-term treatment with renin-angiotensin-aldosterone system blockers, which decrease negative remodeling effects and changes in the levels of the studied serological markers.

1. Laksono S., Prameswari P. Serdechnaya nedostatochnost’ s sokhranonnoy fraktsiyey vybrosa − diagnostika i lecheniye: kratkiy obzor literatury [Heart failure with preserved ejection fraction: A short review of diagnosis and management]. CardioSomatika [CardioSomatics]. 2024;15(1):71-79. (In Russ.) doi: 10.17816/CS623815

2. Tsao C.W., Lyass A., Enserro D., et al. Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JACC Heart Fail. 2018;6(8):678-685. doi: 10.1016/j.jchf.2018.03.006.

3. Agostini L.D.C., Silva N.N.T., Lopes A.C.F., et al. G Protein Subunit Beta 3 (GNB3) Variant Is Associated with Biochemical Changes in Brazilian Patients with Hypertension. Arq Bras Cardiol. 2023;120(12):e20230396. Portuguese, English. doi: 10.36660/abc.20230396.

4. Katsukunya J.N., Soko N.D., Naidoo J., et al. Pharmacogenomics of Hypertension in Africa: Paving the Way for a PharmacogeneticBased Approach for the Treatment of Hypertension in Africans. Int J Hypertens. 2023;2023:9919677. doi: 10.1155/2023/9919677.

5. Dewi I.P., Wardhani L.F.K., Maghfirah I., et al. Association polymorphism of guanine nucleotide-binding protein β3 subunit (GNB3) C825T and insertion/deletion of the angiotensin-converting enzyme (ACE) gene with peripartum cardiomyopathy. Front Cardiovasc Med. 2023;10:1096514. doi: 10.3389/fcvm.2023.1096514.

6. Wang J., Gareri C., Rockman H.A. G-Protein-Coupled Receptors in Heart Disease. Circ Res. 2018;123(6):716-735. doi: 10.1161/CIRCRESAHA.118.311403. Erratum in: Circ Res. 2018;123(10):e34. doi: 10.1161/RES.0000000000000235.

7. Peitz T., Möhlendick B., Siffert W., et al. GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant. Int J Mol Sci. 2022;23(17):9783. doi: 10.3390/ijms23179783.

8. Bhatnagar V., O’Connor D.T., Brophy V.H., et al. G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions. Am J Hypertens. 2009;22(3):332-8. doi: 10.1038/ajh.2008.341.

9. Bagos P.G., Elefsinioti A.L., Nikolopoulos G.K., Hamodrakas S.J. The GNB3 C825T polymorphism and essential hypertension: a metaanalysis of 34 studies including 14,094 cases and 17,760 controls. J Hypertens. 2007;25(3):487-500. doi: 10.1097/HJH.0b013e328011db24.

10. Fu H., Guo C., Zhang J., et al. Associations between the polymorphisms of main components in PI3K/Akt pathway and risk of diabetic kidney disease: A meta-analysis. IUBMB Life. 2023;75(7):624-642. doi: 10.1002/iub.2711. Erratum in: IUBMB Life. 2024;76(2):103. doi: 10.1002/iub.2780.

11. Frey U.H., Moebus S., Möhlenkamp S., et al. GNB3 gene 825 TT variant predicts hard coronary events in the population-based Heinz Nixdorf Recall study. Atherosclerosis. 2014;237(2):437-42. doi: 10.1016/j.atherosclerosis.2014.08.025.

12. Semplicini A., Grandi T., Sandonà C., et al. G-Protein β3-Subunit Gene C825T Polymorphism and Cardiovascular Risk: An Updated Review. High Blood Press Cardiovasc Prev. 2015;22(3):225-32. doi: 10.1007/s40292-015-0093-4.

13. Kokh N.V., Slepukhina A.A., Lifshits G.I. Arterial’naya gipertoniya: molekulyarno-geneticheskiye i farmakogeneticheskiye podkhody [Arterial hypertension: molecular-genetic and pharmacogenetic approaches]. Farmakogenetika i farmakogenomika [Pharmacogenetics and Pharmacogenomics]. 2015;(2):4-8. (In Russ.).

14. Nikitin A.G. Issledovaniye assotsiatsii ryada genov-kandidatov s ishemicheskoy bolezn’yu serdtsa. Avtoreferat. dissertatsii na soiskaniye uchenoy stepeni k.b.n. [Study of the association of several candidate genes with ischemic heart disease. Abstract of a dissertation for the degree of PhD in Biology].2008. (In Russ.)

15. Gou Q., Zhao Q., Dong M., et al. Diagnostic potential of energy metabolism-related genes in heart failure with preserved ejection fraction. Front Endocrinol (Lausanne). 2023;14:1296547. doi: 10.3389/fendo.2023.1296547.

16. Pyvovar S.M., Rudyk Yu.S., Lozyk T.V., Galchinska V.Yu. Polymorphism of c825t (rs5443) gprotein b3-subunit gene and the long-term prognosis for patients with heart failure. Свiт медицини та бiологii. 2019. 15(1):88–3.

17. Moselhy S.S., Alhetari Y.A., Iyer A., et al. Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects. Afr Health Sci. 2017;17(4):1059-1069. doi: 10.4314/ahs.v17i4.14.

18. Siffert W. Molecular genetics of G proteins and atherosclerosis risk. Basic Res Cardiol. 2001;96(6):606-11. doi: 10.1007/s003950170012.

19. İpekoğlu G., Apaydın N., Çetin T., et al. Examining the relationship between genetic polymorphisms (BDKRB2, GNB3, HIF1A, MCT1, NOS3) and endurance athlete status. Eur J Appl Physiol. 2024;124(7):1943-1958. doi: 10.1007/s00421-024-05498-z.

20. Ko K.D., Kim K.K., Suh H.S., Hwang I.C. Associations between the GNB3 C825T polymorphism and obesity-related metabolic risk factors in Korean obese women. J Endocrinol Invest. 2014;37(11):1117-20. doi: 10.1007/s40618-014-0182-6.

21. Nagay A. V., Khamidullayeva G. A., Abdullayeva G. ZH. S825T polimorfizm gena GNB3 i solechuvstvitel’nost’ u bol’nykh esentsial’noy gipertenziyey. II mezhdunarodnyy kongress kardiologiya na perekrestke nauk: Tez. dokl. [C825T polymorphism of the GNB3 gene and salt sensitivity in patients with essential hypertension. II International Congress of Cardiology at the Crossroads of Sciences: Abstract].2011. 2 (In Russ.)

22. Chukaeva I.I., Orlova N.V., Alyautdinova I.A., et al. Izucheniye geneticheskoy obuslovlennosti razvitiya solechuvstvitel’noy arterial’noy gipertonii [Research of genetic conditionality of development of salt-sensitive arterial hypertension]. Meditsinskiy alfavit [Medical alphabet]. 2017;2(34):33-38. (In Russ.)

23. Birkner S., Möhlendick B., Wilde B., et al. Single-Nucleotide Polymorphism in Genes Encoding G Protein Subunits GNB3 and GNAQ Increase the Risk of Cardiovascular Morbidity among Patients Undergoing Renal Replacement Therapy. Int J Mol Sci. 2023;24(20):15260. doi: 10.3390/ijms242015260.

24. Li H.L., Zhang Y.J., Chen X.P., et al. Association between GNB3 c.825C > T polymorphism and the risk of overweight and obesity: A meta-analysis. Meta Gene. 2016;9:18-25. doi: 10.1016/j.mgene.2016.03.002.

25. Arutyunyan L.V. Perspektivy ispol’zovaniya polimorfizma genov dlya opredeleniya prognoza i taktiki lecheniya bol’nykh arterial’noy gipertenziyey: avtoref. dis. … kand. med. Nauk [Prospects for using gene polymorphism to determine the prognosis and treatment tactics for patients with arterial hypertension: Abstract of a PhD thesis]. Moscow, 2020. (In Russ.)