Effect of components of the renin-angiotensin system, rs2106809 polymorphism of the ACE2 gene, and therapy with RAS blockers on the severity of COVID-19

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a key component of the renin-angiotensin system (RAS), providing counter-regulation of its effects and, simultaneously, a receptor for the SARS-CoV-2 entering. It is suggested that factors regulating the balance of the major components of RAS, including ACE2 gene polymorphism, therapy with RAS blockers (ACE inhibitors and angiotensin receptor blockers) — may affect the severity of COVID-19.
AIM: The aim of the study was to investigate the effect of RAS components, the relationship of ACE2 gene polymorphism rs2106809 and ACEi/ARBs therapy with the COVID-19 severity.
MATERIALS AND METHODS: The study included patients with COVID-19 hospitalized in Endocrinology research centre (n = 173), who were divided into groups of moderate and severe course. Determination of RAS components was performed by ELISA, identification of polymorphism by PCR. Statistical analysis was performed using nonparametric statistical methods; differences in the distribution of genotype frequencies were assessed using Fisher’s exact test χ².
RESULTS: The groups differed significantly in age, blood glucose levels, and inflammatory markers: leukocytes, neutrophils, IL-6, D-dimer, C-reactive protein, ferritin and liver enzymes, which correlated with the severity of the disease. When comparing patients in terms of ACE, ACE2, angiotensin II, ADAM17 there were no statistically significant differences between the groups (p=0.544, p=0.054, p=0.836, p=1.0, respectively), including the distribution by gender (in men: p=0.695, p=0.726, p=0.824, p=0.512; in women: p=0.873, p=0.196, p=0.150, p=0.937). Analysis of the distribution of AA, AG, and GG genotypes of the rs2106809 polymorphism of the ACE2 gene also revealed no differences between patients: χ² 1.35, p=0.071 in men, χ² 5.28, p=0.244 in women. There were no significant differences in the use of RAS blockers between groups with different course severity: χ² 0.208, p=0.648 for ACEi, χ² 1.15, p=0.283 for ARBs.
CONCLUSION: In our study, the influence of activation of RAS components (ACE, ACE2, AT II, ADAM17) and ACE2 gene polymorphism on the severity of COVID-19 course was not confirmed. The severity of COVID-19 course correlated with the level of standard inflammatory markers, indicating the general principles of the infection as a systemic inflammation, regardless of the genetic and functional status of the RAS.

1. Walls AC, Park Y-J, et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2):281-292.e6. doi: https://doi.org/10.1016/j.cell.2020.02.058

2. Vikulova OK, Zuraeva ZT, Nikankina LV, Shestakova MV. The role of renin-angiotensin system and angiotensinconverting enzyme 2 (ACE2) in the development and course of viral infection COVID-19 in patients with diabetes mellitus. Diabetes mellitus. 2020;23(3):242-249. (In Russ.). doi: https://doi.org/10.14341/DM12501

3. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52(1):11-34.

4. Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol. 2007;292(1): C82-C97. doi: https://doi.org/10.1152/ajpcell.00287.2006

5. Xie X, Chen J, Wang X, et al. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78(19):2166-2171. doi: https://doi.org/10.1016/j.lfs.2005.09.038

6. Rice GI, Jones AL, Grant PJ, et al. Circulating activities of angiotensinconverting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension. 2006;48(5):914-920. doi: https://doi.org/10.1161/01.HYP.0000244543.91937.79

7. Lu N, Yang Y, Wang Y, et al. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects. Mol Biol Rep. 2012;39(6):6581-6589. doi: https://doi.org/10.1007/s11033-012-1487-1

8. Chen YY, Zhang P, Zhou XM, et al. Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites. J Clin Pharm Ther. 2018;43(2):189-195. doi: https://doi.org/10.1111/jcpt.12625

9. Danser AHJ, Epstein M, Batlle D. Renin-angiotensin system blockers and the COVID-19 pandemic: At present there is no evidence to abandon renin-angiotensin system blockers. Hypertension. 2020;75(6):1382-1385. doi: https://doi.org/10.1161/HYPERTENSIONAHA.120.15082

10. Ministerstvo zdravoohraneniya Rossijskoj Federacii. Vremennye metodicheskie rekomendacii. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infekcii (COVID-19). (In Russ.). Доступно по: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/060/193/original/%D0%92%D0%9C%D0%A0_COVID-19_V16.pdf. 25.11.2022.

11. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94(2):91-95. doi: https://doi.org/10.1016/j.ijid.2020.03.017

12. Heurich A, Hofmann-Winkler H, Gierer S, et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88(2):1293-1307. doi: https://doi.org/10.1128/JVI.02202-13

13. Cariou B, Hadjadj S, Wargny M, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63(8):1500-1515. doi: https://doi.org/10.1007/s00125-020-05180-x

14. Liu D, Chen Y, Zhang P, et al. Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients. Medicine (Baltimore). 2016;95(24):e3876. doi: https://doi.org/10.1097/MD.0000000000003876

15. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550(7675):244-248. doi: https://doi.org/10.1038/nature24265

16. Chen F, Zhang Y, Li X, et al. The impact of ACE2 polymorphisms on COVID-19 disease: susceptibility, severity, and therapy. Front Cell Infect Microbiol. 2021;11(8):1500-1515. doi: https://doi.org/10.3389/fcimb.2021.753721

17. Karakas Çelik S, Çakmak Genç G, Pişkin N, et al. Polymorphisms of ACE (I/D) and ACE2 receptor gene (Rs2106809, Rs2285666) are not related to the clinical course of COVID-19: A case study. J Med Virol. 2021;93(10):5947-5952. doi: https://doi.org/10.1002/jmv.27160

18. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671-1681. doi: https://doi.org/10.1161/CIRCRESAHA.120.317134

19. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. doi: https://doi.org/10.1038/nature02145

20. Mokrysheva NG, Shestakova MV, Vikulova OK, et al. Analysis of risk factors for COVID-19-related fatal outcome in 337991 patients with type 1 and type 2 diabetes mellitus in 2020–2022 years: Russian nationwide retrospective study. Diabetes Mellitus. 2022;25(5):470-483. (In Russ.). doi: https://doi.org/10.14341/DM12954