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Association between angiotensin-converting enzyme-2 gene polymorphism (rs2106809) with severity and outcome of COVID-19 infection

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Abstract

Purpose

Genetic factors play important role in the severity of the COVID-19 infection since SARS-CoV-2 binds to the ACE2 receptor on the surface of host cells. ACE2 polymorphisms that may influence the expression of ACE2 can alter patients’ susceptibility to COVID-19 infection or increase the severity of the disease. This study aimed to investigate the association between ACE2 rs2106809 polymorphism and the severity of the COVID-19 infection.

Methods

In this cross-sectional study, ACE2 rs2106809 polymorphism was assessed in 142 COVID-19 patients. The disease was confirmed according to clinical symptoms, imaging, and laboratory findings. The severity of the disease was graded as severe versus non-severe based on the CDC. Genomic DNA was extracted from the whole blood and PCR- RFLP was performed to genotype the ACE2-rs2106809 with specific primers and Taq1 restriction enzyme.

Results

G/G genotype was significantly associated with COVID-19 severity (44.4% in severe vs. 17.5% in non-severe, OR: 4.1; 95%CI: 1.8–9.5, p = 0.0007). Patients with the G/G genotype need more mechanical ventilation (p = 0.021). ACE2 expression in patients carrying the A/G genotype was higher in the severe compared to the non-severe form of the disease (2.99 ± 0.99 vs. 2.21 ± 1.1), but it was not statistically significant (p = 0.9).

Conclusion

The G allele and G/G genotype of ACE2 rs2106809 is associated with more severe COVID-19 and adverse disease outcomes.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

References

  1. Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA et al (2020) The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5(4):536–544. https://doi.org/10.1038/s41564-020-0695-z

    Article  CAS  Google Scholar 

  2. Organization WH (2021) COVID-19 weekly epidemiological update, 4 May 2021

  3. Yeo C, Kaushal S, Yeo D (2020) Enteric involvement of coronaviruses: is faecal–oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol 5(4):335–337

    Article  PubMed  PubMed Central  Google Scholar 

  4. Alhazzani W, Møller M, Arabi Y, Loeb M, Gong M, Fan E, Du B (2020) Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med 1–34. https://doi.org/10.1007/s00134-020-06022-5

  5. Wang EA, Zenilman J, Brinkley-Rubinstein L (2020) Ethical considerations for COVID-19 vaccine trials in correctional facilities. JAMA 324(11):1031–1032. https://doi.org/10.1001/jama.2020.15589

    Article  CAS  PubMed  Google Scholar 

  6. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y et al (2020) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine 8(5):475–481. https://doi.org/10.1016/S2213-2600(20)30079-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oladejo BO, Adeboboye CF, Adebolu TT (2020) Understanding the genetic determinant of severity in viral diseases: a case of SARS-Cov-2 infection. Egyptian Journal of Medical Human Genetics 21(1):1–11. https://doi.org/10.1186/s43042-020-00122-z

  8. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q (2020) Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367(6485):1444-8. DOI: https://doi.org/10.1126/science.abb2762

  9. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H et al (2020) Structural basis of receptor recognition by SARS-CoV-2. Nature 581(7807):221–224. https://doi.org/10.1038/s41586-020-2179-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bestle D, Heindl MR, Limburg H, Pilgram O, Moulton H, Stein DA et al (2020) TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci alliance 3(9). https://doi.org/10.26508/lsa.202000786

  11. Zhu L, She Z, Cheng X, Qin J, Zhang X, Cai J et al (2019) Wang W Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2:1068-77. https://doi.org/10.1016/j.cmet.2020.04.021

  12. Devaux CA, Pinault L, Osman IO, Raoult D (2021) Can ACE2 receptor polymorphism predict species susceptibility to SARS-CoV-2? Front Public Health 930. https://doi.org/10.3389/fpubh.2020.608765

  13. Chiu RW, Tang NL, Hui DS, Chung GT, Chim SS, Chan KA et al (2004) ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem 50(9):1683–1686. https://doi.org/10.1373/clinchem.2004.035436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Elemam NM, Hasswan H, Aljaibeji H, Sulaiman N (2021) Circulating soluble ACE2 and upstream microRNA expressions in serum of type 2 diabetes mellitus patients. Int J Mol Sci 22(10):5263. https://doi.org/10.3390/ijms22105263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu C, Li Y, Guan T, Lai Y, Shen Y, Zeyaweiding A et al (2018) ACE2 polymorphisms associated with cardiovascular risk in uygurs with type 2 diabetes mellitus. Cardiovasc Diabetol 17(1):1–11

    Article  Google Scholar 

  16. Sabater Molina M, Nicolás Rocamora E, Bendicho AI, Vázquez EG, Zorio E, Rodriguez FD et al (2022) Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease. PLoS ONE 17(2):e0263140. https://doi.org/10.1371/journal.pone.0263140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pouladi N, Abdolahi S (2021) Investigating the ACE2 polymorphisms in COVID-19 susceptibility: an in silico analysis. Mol Genet Genom Med 9(6):e1672. https://doi.org/10.1002/mgg3.1672

    Article  CAS  Google Scholar 

  18. Patel S, Rauf A, Khan H, Abu-Izneid T (2017) Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies. Biomed Pharmacother 94:317–325. https://doi.org/10.1016/j.biopha.2017.07.091

  19. Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M et al (2017) The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). https://doi.org/10.1152/physrev.00023.2016. Physiological reviews

  20. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B et al (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med 11(8):875–879. https://doi.org/10.1038/nm1267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M et al (2020) SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 26(5):681–687. https://doi.org/10.1038/s41591-020-0868-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. https://www.ncbi.nlm.nih.gov/snp/rs2106809#variant_details

  23. Devaux CA, Rolain J-M, Raoult D (2020) ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J Microbiol Immunol Infect 53(3):425–435. https://doi.org/10.1016/j.jmii.2020.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. https://www.cdc.gov/

  25. Karakaş Çelik S, Çakmak Genç G, Pişkin N, Açikgöz B, Altinsoy B, Kurucu İşsiz B et al (2021) 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 93(10):5947–5952. https://doi.org/10.1002/jmv.27160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Suleiman A, Rafaa T, Alrawi A, Dawood M (2021) The impact of ACE2 genetic polymorphisms (rs2106809 and rs2074192) on gender susceptibility to COVID-19 infection and recovery: a systematic review. Baghdad J Biochem Appl Biol Sci 2(03):167–180. https://doi.org/10.47419/bjbabs.v2i03.53

    Article  CAS  Google Scholar 

  27. Oudit G, Kassiri Z, Jiang C, Liu P, Poutanen S, Penninger J et al (2009) SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 39(7):618–625. https://doi.org/10.1111/j.1365-2362.2009.02153.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen F, Zhang Y, Li X, Li W, Liu X, Xue X (2021) The impact of ACE2 polymorphisms on COVID-19 Disease: susceptibility, severity, and Therapy. Front Cell Infect Microbiol 1002. https://doi.org/10.3389/fcimb.2021.753721

  29. Cafiero C, Rosapepe F, Palmirotta R, Re A, Ottaiano MP, Benincasa G et al (2021) Angiotensin system polymorphisms’ in SARS-CoV-2 positive patients: assessment between symptomatic and asymptomatic patients: a pilot study. Pharmacogenomics and Personalized Medicine 14:621. https://doi.org/10.2147/PGPM.S303666

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bosso M, Thanaraj TA, Abu-Farha M, Alanbaei M, Abubaker J, Al-Mulla F (2020) The two faces of ACE2: the role of ACE2 receptor and its polymorphisms in hypertension and COVID-19. Mol Therapy-Methods Clin Dev 18:321–327. https://doi.org/10.1016/j.omtm.2020.06.017

    Article  CAS  Google Scholar 

  31. Sieńko J, Kotowski M, Bogacz A, Lechowicz K, Drożdżal S, Rosik J et al (2020) COVID-19: the influence of ACE genotype and ACE-I and ARBs on the course of SARS-CoV-2 infection in elderly patients. Clin Interv Aging 15:1231

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all patients and their families and also the staff of Imam Hospital for their cooperation in the collecting of samples and information.

Funding

This study was funded by Mazandaran University of Medical Sciences [Grant No.7758].

Author information

Authors and Affiliations

  1. Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Hamideh Mohammadi-Berenjestanaki, Elaheh Mohammadali, Mina Khasayesi, Zahra Kashi, Narges Mirzaei-Ilali & Zahra Hosseini-khah

  2. Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Alireza Rafiei

Authors
  1. Hamideh Mohammadi-Berenjestanaki
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  2. Elaheh Mohammadali
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  3. Mina Khasayesi
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  6. Narges Mirzaei-Ilali
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  7. Zahra Hosseini-khah
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Contributions

All authors contributed to the study’s conception and design. Hamideh Mohammadi contributed to data collection and wrote the manuscript. Elaheh Mohammadali and Mina Khasayesi carried out the assays, contributed to data collection, and wrote the manuscript. Alireza Rafiei contributed to data analysis and revise the manuscript for important intellectual content. Zahra Kashi supervised the work and revised the manuscript. Narges Mirzaei Ilali provided the samples and contributed to data collection. Zahra Hosseini-khah designed and conducted the research. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zahra Hosseini-khah.

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Conflict of interest

The authors declare no conflict of interest.

Ethics approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the ethical standards of the Mazandaran University of Medical Sciences (Ethics Committee Code: IR.MAZUMS.REC.1399.7758).

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Informed consent was obtained from all subjects involved in the study.

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Mohammadi-Berenjestanaki, H., Mohammadali, E., Khasayesi, M. et al. Association between angiotensin-converting enzyme-2 gene polymorphism (rs2106809) with severity and outcome of COVID-19 infection. Mol Biol Rep 50, 6669–6679 (2023). https://doi.org/10.1007/s11033-023-08493-3

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  • DOI: https://doi.org/10.1007/s11033-023-08493-3

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