The impact of ACE2 genetic polymorphisms (rs2106809 and rs2074192) on gender susceptibility to COVID-19 infection and recovery: A systematic review


  • Ahmed A. Suleiman Department of Biotechnology, College of Science, University of Anbar, Ramadi, Iraq
  • Tamadher A. Rafaa The Presidency of the University of Anbar, Ramadi, Iraq
  • Ali M. Al­rawi Department of Biotechnology, College of Science, University of Anbar, Ramadi, Iraq
  • Mustafa F. Dawood College of Education for Pure Science, University of Anbar, Ramadi, Iraq



ACE2, COVID-19, gene polymorphism, gender, SARS-CoV-2


Background: Epidemiological studies revealed there is a difference in susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of differences in gender with age and males being more inflicted. There is a clear indication that deaths caused by coronavirus disease 2019 (COVID-19) in males appeared at a higher rate than females across 35 nations. The implication of associated disease-risk genes, involved in the susceptibility of COVID-19 such as the angiotensin-converting enzyme 2 (ACE2), has recently received considerable attention due to their role in severe injury of lung and mediated SARS-CoV-2 entry as a host receptor.

Objectives: Herein, we aimed to systematically review how two main genetic polymorphisms of ACE2 (rs2106809 and rs2074192) can affect the gender susceptibility to SARS-CoV-2 infection.

Methods: To conduct this systematic review, a literature search in PubMed, Google Scholar, ScienceDirect, and Nature was made for the period 2004 to 2020. We searched for the impact of ACE2 genetic polymorphisms (rs2106809 and rs2074192) on gender susceptibility.

Results: We noticed that there was a differential genotype distribution between males and females in various global populations whereas mutant variants were common in males compared to wild-type variants among females, which may reflect differences in gender susceptibility to infection with SARS-CoV-2. Females are less susceptible to coronavirus as compare to males because of the expression of ACE2 receptor. It has a double role in favour of COVID-19 and against COVID-19.

Conclusions: Male mortality is greater than female mortality, which might be attributed to the ACE2 deficiency in women. Epidemiological studies have shown that the differences in sex and age have different susceptibility to SARS-CoV-2 infection.


Download data is not yet available.


A Fernández-Atucha, A Izagirre, and A B Fraile-Bermúdez. “Sex differences in the aging pattern of renin-angiotensin system serum peptidases”. Biol Sex Differ 8(1) (2017), pp. 1–8. DOI: 10.1186/s13293-017-0128-8.

A M Horstman et al. “The role of androgens and estrogens on healthy aging and longevity”. Journals Gerontol - Ser A Biol Sci Med Sci 67(11) (2012), pp. 1140–1152. DOI: 10.1093/gerona/gls068.

A R Bourgonje, A E Abdulle, and W Timens. “Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19)”. J Pathol 251(3) (2020), pp. 228–248. DOI: 10.1002/path.5471.

Anum S. Minhas et al. “Takotsubo Syndrome in the Setting of COVID-19”. JACC Case Rep 2(9) (2020), pp. 1321–1325. DOI: 10.1016/j.jaccas.2020.04.023.

C Penna et al. “Sex-related differences in COVID-19 lethality”. Br J Pharmacol 177(19) (2020), pp. 4375–4385. DOI: 10.1111/bph.15207.

D Gemmati et al. “COVID-19 and individual genetic susceptibility/receptivity: Role of ACE1/ACE2 genes, immunity, inflammation and coagulation. might the double x-chromosome in females be protective against SARS-COV-2 compared to the single x-chromosome in males?” Int J Mol Sci 21(10) (2020), pp. 1–23. DOI: 10.3390/ijms21103474.

E Ciaglia, C Vecchione, and A A Puca. “COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Women and Children”. Front Pediatr 8 (2020), pp. 11–13. DOI: 10.3389/fped.2020.00206.

H Zhang and A Baker. “Recombinant human ACE2: Acing out angiotensin II in ARDS therapy”. Crit Care 21(1) (2017), pp. 4–6. DOI: 10.1186/s13054-017-1882-z.

Iziah E Sama et al. “Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors”. Eur Heart J 41(19) (2020), pp. 1810–1817. DOI: 10.1093/eurheartj/ehaa373.

J L Grobe, B A Buehrer, and A M Hilzendeger. “Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice”. Hypertension 57(3 PART 2) (2011), pp. 600–607. DOI: 10.1161/HYPERTENSIONAHA.110.165829.

J M Jin, P Bai, and W He. “Gender Differences in Patients With COVID-19: Focus on Severity and Mortality”. Front Public Heal 8 (2020), pp. 1–6. DOI: 10.3389/fpubh.2020.00152.

J Ramchand et al. “Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease”. PLoS One 13(6) (2018), pp. 1–11. DOI: 10.1371/journal.pone.0198144.

Ja-S Salman et al. “The Effectiveness of Probiotics against Viral Infections: A Rapid Review with Focus on SARS-CoV-2 Infection. Open Access Maced”. J Med Sci 8(T1) (2020), pp. 496–508. DOI: 10.3889/oamjms.2020.5483.

K Kuba, Y Imai, and S Rao. “A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury”. Nat Med 11(8) (2005), pp. 875–879. DOI: 10.1038/nm1267.

K Pyrc, B Berkhout, and L Van Der Hoek. “Identification of new human coronaviruses”. Expert Rev Anti Infect Ther 5(2) (2007), pp. 245–253. DOI: 10.1586/14787210.5.2.245.

L Malard, L Kakinami, and J O’loughlin. “The association between the angiotensin-converting enzyme-2 gene and blood pressure in a cohort study of adolescents”. BMC Med Genet 14(1) (2013). DOI: 10.1186/1471-2350-14-117.

M C Chappell et al. “Update on the angiotensin converting enzyme 2-angiotensin (1-7)-Mas receptor axis: Fetal programing, sex differences, and intracellular pathways”. Front Endocrinol (Lausanne) 5 (2014), pp. 1–13. DOI: 10.3389/fendo.2013.00201.

M C Gagliardi et al. “ACE2 expression and sex disparity in COVID-19”. Cell Death Discov 6(1) (2020), pp. 1–2. DOI: 10.1038/s41420-020-0276-1.

M Donoghue, F Hsieh, and E Baronas. “A Novel Angiotensin-Converting Enzyme - Related to Angiotensin 1-9”. Circ Res 87(5) (2000), pp. 1–10.

M Gheblawi, K Wang, and A Viveiros. “Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2”. Circ Res. Published (2020), pp. 1456–1474. DOI: 10.1161/CIRCRESAHA.120.317015.

M Hoffmann, H Kleine-Weber, and S Schroeder. “SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor”. Cell 181(2) (2020), pp. 271–280. DOI: 10.1016/j.cell.2020.02.052.

M Houssen et al. “Association of ACE and ACE2 Genes Polymorphisms With Susceptibility To Hepatocellular Carcinoma in Egyptian HCV Patients”. J Glob Biosci 4 (2015), pp. 2393–2403.

M Patnaik et al. “Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha”. Ann Hum Biol 41(2) (2013), pp. 145–152. DOI: 10.3109/03014460.2013.837195.

N Chen, M Zhou, and X Dong. “Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study”. Lancet 395 (2020), pp. 507–513. DOI: 10.1016/S0140-6736(20)30211-7.

N Dhochak et al. “Pathophysiology of COVID-19: Why Children Fare Better than Adults?” Indian J Pediatr 87(7) (2020), pp. 537–546. DOI: 10.1007/s12098-020-03322-y.

P Cheng, H Zhu, and R M Witteles. “Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty”. Curr Cardiol Rep 22(5) (2020), pp. 1–6. DOI: 10.1007/s11886-020-01293-2.

P Conti and A Younes. “Coronavirus cov-19/sars-cov-2 affects women less than men: Clinical response to viral infection”. J Biol Regul Homeost Agents 34(2) (2020), pp. 339–343. DOI: 10.23812/Editorial-Conti-3.

P Fagone, R Ciurleo, and S D Lombardo. “Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies”. Autoimmun Rev 19(7) (2020), pp. 102571–102571. DOI: 10.1016/j.autrev.2020.102571.

P K Datta et al. “SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy”. Theranostics 10(16) (2020), pp. 7448–7464. DOI: 10.7150/thno.48076.

Renin-Angiotensin-Aldosterone Syst 16(2) (2015), pp. 249–253. DOI: 10.1177/1470320315576256.

S Fisher, A Barry, and J Abreu. “A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries”. Genome Biol 12(1) (2011), pp. 1–15. DOI: 10.1186/gb-2011-12-1-r1.

S Ghafouri-Fard et al. “Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection”. Vascul Pharmacol 130(106680) (2020). DOI: 10.1016/j.vph.2020.106680.

S Ghosh and R S Klein. “Sex Drives Dimorphic Immune Responses to Viral Infections”. J Immunol 198(5) (2017), pp. 1782–1790. DOI: 10.4049/jimmunol.1601166.

S K Patel, B Wai, and M Ord. “Association of ACE2 genetic variants with blood pressure, left ventricular mass, and cardiac function in caucasians with type 2 diabetes”. Am J Hypertens 25(2) (2012), pp. 216–222. DOI: 10.1038/ajh.2011.188.

S Wakahara, T Konoshita, and S Mizuno. “Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio”. Endocrinology 148(5) (2007), pp. 2453–2457. DOI: 10.1210/en.2006-1287.

S X Wang et al. “Polymorphisms of angiotensin-converting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy”. Chin Med J (Engl) 121(1) (2008), pp. 27–31.

T Behl, I Kaur, and S Bungau. “The dual impact of ACE2 in COVID-19 and ironical actions in geriatrics and pediatrics with possible therapeutic solutions”. Life Sci 257 (2020), pp. 118075–118075. DOI: 10.1016/j.lfs.2020.118075.

V B Patel et al. “Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure”. Circ Res 118(8) (2016), pp. 1313–1326. DOI: 10.1161/CIRCRESAHA.116.307708.

V Monteil, H Kwon, and P Prado. “Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2”. Cell 181(4) (2020), pp. 905–913. DOI: 10.1016/j.cell.2020.04.004.

W Tan and J Aboulhosn. “The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease”. Int J Cardiol 309 (2020), pp. 70–77. DOI: 10.1016/j.ijcard.2020.03.063.

X Xudong et al. “Age- and gender-related difference of ACE2 expression in rat lung”. Life Sci 78(19) (2006), pp. 2166–2171. DOI: 10.1016/j.lfs.2005.09.038.

Y Chen, Q Liu, and D Guo. “Emerging coronaviruses: Genome structure, replication, and pathogenesis”. J Med Virol 92(4) (2020), pp. 418–423. DOI: 10.1002/jmv.25681.

Y Imai, K Kuba, and S Rao. “Angiotensin-converting enzyme 2 protects from severe acute lung failure”. Nature 436(7047) (2005), pp. 112–116. DOI: 10.1038/nature03712.

Y M Yuan et al. “Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats”. JRAAS - J

Yu Zhao et al. “Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2”. bioRxiv (2020). DOI: 10.1101/2020.01.26.919985.




How to Cite

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 Journal of Biochemistry and Applied Biological Sciences, 2(03), 166–179.