Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications

doi:10.1007/s10096-021-04264-9

Review

. 2021 Aug;40(8):1587-1598.

doi: 10.1007/s10096-021-04264-9. Epub 2021 May 3.

Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications

Anvarsadat Kianmehr^{1

2}, Isabella Faraoni³, Omer Kucuk⁴, Abdolkarim Mahrooz^{5

6}

Affiliations

¹ Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
² Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
³ Department of Systems Medicine, University of Rome Tor Vergata, 00173, Rom, Italy.
⁴ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
⁵ Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. amahrooz@mazums.ac.ir.
⁶ Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran. amahrooz@mazums.ac.ir.

PMID: 33939044
PMCID: PMC8091148
DOI: 10.1007/s10096-021-04264-9

Review

Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications

Anvarsadat Kianmehr et al. Eur J Clin Microbiol Infect Dis. 2021 Aug.

. 2021 Aug;40(8):1587-1598.

doi: 10.1007/s10096-021-04264-9. Epub 2021 May 3.

Authors

Anvarsadat Kianmehr^{1

2}, Isabella Faraoni³, Omer Kucuk⁴, Abdolkarim Mahrooz^{5

6}

Affiliations

¹ Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
² Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
³ Department of Systems Medicine, University of Rome Tor Vergata, 00173, Rom, Italy.
⁴ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
⁵ Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. amahrooz@mazums.ac.ir.
⁶ Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran. amahrooz@mazums.ac.ir.

PMID: 33939044
PMCID: PMC8091148
DOI: 10.1007/s10096-021-04264-9

Abstract

Receptor recognition is a crucial step in viral infection and is a critical factor for cell entry and tissue tropism. In several recent studies, angiotensin-converting enzyme 2 (ACE2) has been demonstrated to be the cellular receptor of SARS-CoV-2 as it was previously well known as the receptor of SARS-CoV. SARS-CoV-2 can bind with high affinity to human ACE2 and engages it as an entry receptor. It seems that the genetic, notably epigenetic variations of ACE2 are less known in different populations, indicating the need for its further investigation. These variations have the potential to affect its contribution to the pathogenicity of COVID-19. The contribution of epigenetics in the interindividual variability of ACE2 merits more attention because epigenetic processes can play important roles in ACE2 alterations in various tissues and different people and populations. Analyzing different DNA methylation patterns and microRNAs, contributing to the ACE2 modulation in the lungs will have a high priority. The epigenetic and genetic variations of ACE2 become even more important when considering that some people have mild clinical symptoms despite having COVID-19. The pathogenicity of SARS-CoV-2 infection is complex; therefore, a better understanding of the underlying pathobiology, especially binding the virus to its receptors, could help improve therapeutic and preventive approaches. This review aims to highlight the importance of evaluating both the epigenetic and genetic variations of ACE2 as a receptor for the deadly SARS-CoV-2.

Keywords: ACE2; Angiotensin-converting enzyme 2; COVID-19; Epigenetics; Genetic variation; SARS-CoV-2.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
An overview of the epigenetic and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2. The epigenetic and genetic variations of ACE2 need to be considered together to better understand the various factors that contribute to regulating this crucial enzyme

See this image and copyright information in PMC

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References

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[1] Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB (2020) Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A Review. JAMA. - PubMed

[2] Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB (2020) Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A Review. JAMA. - PubMed

[3] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. - PMC - PubMed

[4] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. - PMC - PubMed

[5] Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Phys Lung Cell Mol Phys. 2018;314(1):L17–L31. - PMC - PubMed

[6] Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Phys Lung Cell Mol Phys. 2018;314(1):L17–L31. - PMC - PubMed

[7] Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, et al. The emerging role of ACE2 in physiology and disease. J Pathol. 2007;212(1):1–11. doi: 10.1002/path.2162. - DOI - PMC - PubMed

[8] Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, et al. The emerging role of ACE2 in physiology and disease. J Pathol. 2007;212(1):1–11. doi: 10.1002/path.2162. - DOI - PMC - PubMed

[9] Burrell LM, Harrap SB, Velkoska E, Patel SK. The ACE2 gene: its potential as a functional candidate for cardiovascular disease. Clin Sci. 2013;124(2):65–76. doi: 10.1042/CS20120269. - DOI - PubMed

[10] Burrell LM, Harrap SB, Velkoska E, Patel SK. The ACE2 gene: its potential as a functional candidate for cardiovascular disease. Clin Sci. 2013;124(2):65–76. doi: 10.1042/CS20120269. - DOI - PubMed

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Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications

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Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications

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