Genotype AA of ACE2 G8790A (rs2285666) Has Protective Potential Against COVID-19 Disease Severity

Sowmya Gayatri Chukkayapalli, Swati Suravaram, Bharat Kumar Reddy, Imran Ahmed Siddiqui


Background: SARS-CoV-2 virus uses angiotensin converting enzyme 2 (ACE2), a key enzyme of the renin angiotensin system (RAS) as the functional receptor for cell fusion and induction of infections in the respiratory system. Functional ACE2 gene polymorphisms may lead to RAS imbalance and are associated with COVID-19 susceptibility and severity. ACE2 G8790A (rs2285666), a splice region variant, is well characterized in various populations across the world. In the present study, the role of ACE2 G8790A (rs2285666) variant as risk predictor for severity of COVID-19 infection was investigated.

Materials and methods: One-hundred COVID-19 subjects were included in the study and divided into: subjects with a history of severe infection and ICU-admitted (Group 1) and subjects with mild to moderate COVID-19 infection (Group 2). Genotype analysis for rs2285666 of ACE2 was performed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.

Results: The distribution of ACE2 G8790A (rs2285666) genotypes were GG 62%, GA 18%, and AA 20% in Group 1 and GG 34%, GA 14%, and AA 52% in Group 2, respectively. The A allele of rs2285666 (p≤0.001; OR=3.4; 95% CI=1.89–6.107) were less frequent in Group 1 as compared to Group 2. Also, a statistically significant difference was found between severity of COVID-19 infection with age and comorbidities such as diabetes, hypertension, chronic kidney disease, but not gender.

Conclusion: Our findings suggest the possibility of a protective mechanism of the AA genotype of ACE2 G8790A (rs2285666) variant against COVID-19 disease severity.

Keywords: COVID-19, ACE2 gene, renin-angiotensin system, genetic association, rs2285666, sanger sequencing

Full Text:



Yang W, Sirajuddin A, Zhang X, Liu G, Teng Z, Zhao S, et al. The role of imaging in 2019 novel coronavirus pneumonia (COVID-19). Eur Radiol. 2020; 30(9): 4874–82, CrossRef.

Li X, Guan B, Su T, Liu W, Chen M, Bin Waleed K, et al. Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: A systematic review and meta-analysis. Heart. 2020; 106(15): 1142–7, CrossRef.

Sabatino J, De Rosa S, Di Salvo G, Indolfi C. Impact of cardiovascular risk profile on COVID-19 outcome. A meta-analysis. PLoS One. 2020; 15(8): e0237131, CrossRef.

Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2): 631–7, CrossRef.

Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020; 117(21): 11727–34, CrossRef.

Li F. Receptor recognition mechanisms of coronaviruses: A decade of structural studies. J Virol. 2015; 89(4): 1954–64, CrossRef.

Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020; 92(4): 418–23, CrossRef.

Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. 2010; 182(8): 1065–72, CrossRef.

Wösten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, et al. acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist: ARDS leads to reduced ratio of ACE/ACE2 activities. J Pathol. 2011; 225(4): 618–27, CrossRef.

Liu Z, Xiao X, Wei X, Li J, Yang J, Tan H, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol. 2020; 92(6): 595–601, CrossRef.

Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020; 63(3): 364–74, CrossRef.

Srivastava A, Bandopadhyay A, Das D, Pandey RK, Singh V, Khanam N, et al. Genetic association of ACE2 rs2285666 polymorphism with COVID-19 spatial distribution in India. Front Genet. 2020; 11: 564741, CrossRef.

Karakaş Çelik S, Çakmak Genç G, Pişkin N, Açikgöz B, Altinsoy B, Kurucu İşsiz B, 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): 5947–52, CrossRef.

Patel SK, Velkoska E, Freeman M, Wai B, Lancefield TF, Burrell LM. From gene to protein-Experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol. 2014; 5: 227, CrossRef.

Pouladi N, Abdolahi S. Investigating the ACE2 polymorphisms in COVID-19 susceptibility: An in-silico analysis. Mol Genet Genomic Med. 2021; 9(6): e1672, CrossRef.

Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020; 6(1): 11, CrossRef.

Hou Y, Zhao J, Martin W, Kallianpur A, Chung MK, Jehi L, et al. New insights into genetic susceptibility of COVID-19: An ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 2020; 18(1): 216, CrossRef.

World Health Organization [Internet]. Weekly Operational Update on COVID-19 - 16 August 2021 [cited 2023 Jul 24]. Available from:

World Health Organization. Living Guidance for Clinical Management of COVID-19. Geneva: World Health Organization; 2021, article.

The PLOS ONE Editors. Expression of Concern: Low-dose chest CT for diagnosing and assessing the extent of lung involvement of SARS-CoV-2 pneumonia using a semi quantitative score. PLoS One. 2022; 17(12): e0279045, CrossRef.

Möhlendick B, Schönfelder K, Breuckmann K, Elsner C, Babel N, Balfanz P, et al. ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19. Pharmacogenet Genomics. 2021; 31(8): 165–71, CrossRef.

Alimoradi N, Sharqi M, Firouzabadi D, Sadeghi MM, Moezzi MI, Firouzabadi N. SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease. Virol J. 2022; 19(1): 48, CrossRef.

Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005; 11(8): 875–9, CrossRef.

Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020; 181(4): 894–904.e9, CrossRef.

Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1–7). Physiol Rev. 2018; 98(1): 505–53, CrossRef.

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020; 12(1): 8, CrossRef.

Li Y, Zeng Z, Cao Y, Liu Y, Ping F, Liang M, et al. Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways. Sci Rep. 2016; 6: 27911, CrossRef.

Magalhaes GS, Barroso LC, Reis AC, Rodrigues-Machado MG, Gregório JF, Motta-Santos D, et al. Angiotensin-(1–7) promotes resolution of eosinophilic inflammation in an experimental model of asthma. Front Immunol. 2018; 9: 58, CrossRef.

Wang D, Chai XQ, Magnussen CG, Zosky GR, Shu SH, Wei X, et al. Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation. Pulm Pharmacol Ther. 2019; 58(101833): 101833, CrossRef.

He H, Liu L, Chen Q, Liu A, Cai S, Yang Y, et al. Mesenchymal stem cells overexpressing angiotensin-converting enzyme 2 rescue lipopolysaccharide-induced lung injury. Cell Transplant. 2015; 24(9): 1699–715, CrossRef.

Bastos AC, Magalhães GS, Gregório JF, Matos NA, Motta-Santos D, Bezerra FS, et al. Oral formulation angiotensin-(1-7) therapy attenuates pulmonary and systemic damage in mice with emphysema induced by elastase. Immunobiology. 2020; 225(2): 151893, CrossRef.

Gironacci MM. Angiotensin-(1–7): Beyond its central effects on blood pressure. Ther Adv Cardiovasc Dis. 2015; 9(4): 209–16, CrossRef.

Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020; 76: 14–20, CrossRef.

Costa LB, Perez LG, Palmeira VA, Macedo e Cordeiro T, Ribeiro VT, Lanza K, et al. Insights on SARS-CoV-2 molecular interactions with the renin-angiotensin system. Front Cell Dev Biol. 2020; 8: 559841, CrossRef.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229): 1033–4, CrossRef.

Wu YH, Li JY, Wang C, Zhang LM, Qiao H. The ACE2 G8790A polymorphism: Involvement in type 2 diabetes mellitus combined with cerebral stroke. J Clin Lab Anal. 2017; 31(2): e22033, CrossRef.

Tandirogang N, Fitriany E, Mardiana N, Jannah M, Dilan BFN, Ratri SR, et al. Neutralizing antibody response by inactivated SARS-CoV-2 vaccine on healthcare workers. Mol Cell Biomed Sci. 2023;7(1): 18-27, CrossRef.

Gómez J, Albaiceta GM, García-Clemente M, López-Larrea C, Amado-Rodríguez L, Lopez-Alonso I, et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene. 2020; 762(145102): 145102, CrossRef.


Copyright (c) 2023 Cell and BioPharmaceutical Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Indexed by:



Cell and BioPharmaceutical Institute