Numerous genetic factors influence the severity and susceptibility to COVID-19. The renin-angiotensin system has a role in the genesis of COVID-19. This study aims to investigate the genetic polymorphisms of Angiotensin-Converting Enzyme Insertion/Deletion (ACE I/D) and ACE2 rs2285666 in patients with COVID-19 and their association with mild, severe, and critical disease symptoms.
Materials and Methods:
This study included 300 patients with COVID-19, categorized as mild, severe, and critical. Genotypes for the I/D polymorphism of ACE1 and the rs2285666 polymorphism of ACE2 were determined in all samples using polymerase chain reaction (PCR) and restriction fragment length polymorphism-PCR methodologies, respectively.
Results:
This study revealed a significant association between the ACEI/D genotype and the severity of COVID-19 (p < 0.001). A strong association was seen between the frequency of ACEI/D alleles and the severity of COVID-19, with the D allele being more prevalent in the severe and critical cohorts compared with the mild cohort (p < 0.001). A significant association was found between the ACE2 rs2285666 polymorphism and disease severity in both male and female groups (p < 0.05). The frequency of G/A alleles linked to the ACE2 polymorphism exhibited a significant association with disease severity, as the G allele was more common in the severe and critical groups than in the mild group (p = 0.004).
Conclusion:
Individuals with the homozygous ACE D/D genotype have an increased susceptibility to severe COVID-19, while the presence of allele I may provide a preventive advantage against severe disease symptoms. The ACE2 rs2285666 variant is associated with disease severity, while the ACE2 G/G genotype is linked to an increased severity of COVID-19.
AladagE, TasZ, OzdemirBS, et al.Human ace D/I polymorphism could affect the clinicobiological course of COVID-19. J Renin Angiotensin Aldosterone Syst, 2021; 2021:1–7.
2.
AyadaC, ToruU, GençO, et al.Evaluation of whether the ACE gene I/D polymorphism constitutes a risk factor for chronic obstructive pulmonary disease in the Turkish population. Genet Mol Res, 2014; 13(4):10427–10433.
3.
BadraouiR, AlrashediMM, El-MayMV, et al.Acute respiratory distress syndrome: A life threatening associated complication of SARS-CoV-2 infection inducing COVID-19. J Biomol Struct Dyn, 2021; 39(17):6842–6851.
4.
CalabreseC, AnnunziataA, CoppolaA, et al.ACE gene I/D polymorphism and acute pulmonary embolism in COVID-19 pneumonia: A potential predisposing role. Front Med (Lausanne), 2021; 7:631148.
5.
ChenN, ZhouM, DongX, et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet, 2020; 395(10223):507–513.
6.
ChenF, ZhangY, LiX, et al.The impact of ACE2 polymorphisms on COVID-19 disease: Susceptibility, severity, and therapy. Front Cell Infect Microbiol, 2021; 11:753721. 1002.
7.
ChmielewskaI, MlakR, KrawczykP, et al.Polymorphism of the ACE gene and the risk of obstructive sleep apnoea. Adv Respir Med, 2013; 81(3):207–213.
8.
de AbajoFJ, Rodríguez-MartínS, LermaV, et al.; MED-ACE2-COVID19 study group. Use of renin–angiotensin the impact of ACE2 polymorphisms on COVID-19 disease: Susceptibility, severity, and therapy.” –Aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: A case-population study. Lancet, 2020; 395(10238):1705–1714.
9.
DelangheJR, SpeeckaertMM, De BuyzereML, et al.COVID-19 infections are also affected by human ACE1 D/I polymorphism. Clin Chem Lab Med, 2020; 58(7):1125–1126.
10.
ElshafeiA, KhidrEG, El-HusseinyAA, et al.RAAS, ACE2 and COVID-19; a mechanistic review. Saudi J Biol Sci, 2021; 28(11):6465–6470.
11.
GómezJ, AlbaicetaGM, García-ClementeM, et al.Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene, 2020; 762:145102.
12.
GómezJ, et al.Angiotensin-converting enzyme (ACE1, ACE2) gene variants are associated with COVID19 severity depending on the hypertension status. MedRxiv, 2020 2020.2006. 2011.20128033.
13.
GuanW-J, et al.China medical treatment expert group for COVID-19. Clinical Characteristics of Coronavirus Disease, 2019; 382(18):1708–1720.
14.
HashemiehM. Epidemiology, transmission methods, clinical manifestations, radiological symptoms, prognosis and treatment of COVID-19 in children. Journal of Arak University of Medical Sciences, 2020; 23(5):654–665.
15.
HenryBM, AggarwalG, WongJ, et al.Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis. Am J Emerg Med, 2020; 38(9):1722–1726.
16.
HülsmannS, KhabbazzadehS, MeissnerK, et al.A potential role of the renin-angiotensin-system for disturbances of respiratory chemosensitivity in acute respiratory distress syndrome and severe acute respiratory syndrome. Front Physiol, 2021; 11:588248.
17.
Karakaş ÇelikS, Çakmak GençG, PişkinN, 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.
18.
KhayatAS, de AssumpçãoPP, Meireles KhayatBC, et al.ACE2 polymorphisms as potential players in COVID-19 outcome. PLoS One, 2020; 15(12):e0243887.
19.
LeeC, ChoiWJ. Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective. Arch Pharm Res, 2021; 44(1):99–116.
20.
LiZ, et al.Caution on kidney dysfunctions of COVID-19 patients. MedRxiv, 2020 2020.2002. 2008.20021212.
21.
LubbeL, CozierGE, OosthuizenD, et al.ACE2 and ACE: Structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Clin Sci (Lond), 2020; 134(21):2851–2871.
22.
MahmoodZS, FadhilHY, Abdul HusseinTA, et al.Severity of coronavirus disease 19: Profile of inflammatory markers and ACE (rs4646994) and ACE2 (rs2285666) gene polymorphisms in Iraqi patients. Meta Gene, 2022; 31:101014.
23.
MalardL, KakinamiL, O’LoughlinJ, et al.The association between the angiotensin-converting enzyme-2 gene and blood pressure in a cohort study of adolescents. BMC Med Genet, 2013; 14(1):117.
24.
MarshallRP, WebbS, BellinganGJ, et al.Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med, 2002; 166(5):646–650.
25.
NajafiM, MahdaviMR. Association investigations between ACE1 and ACE2 polymorphisms and severity of COVID-19 disease. Mol Genet Genomics, 2023; 298(1):27–36.
26.
Razavi NikooH, FatahiSM, TaheriM, et al.A multicentric study of ACE2 rs2285666 polymorphism: The Association with COVID-19 in the Iranian population. Jundishapur J Microbiol, 2024; 17(10):e153765.
27.
RokniM, AhmadikiaK, AsghariS, et al.Comparison of clinical, para-clinical and laboratory findings in survived and deceased patients with COVID-19: Diagnostic role of inflammatory indications in determining the severity of illness. BMC Infect Dis, 2020; 20(1):869.
28.
RokniM, GhasemiV, TavakoliZ, et al.Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS. Rev Med Virol, 2020; 30(3):e2107.
29.
SaengsiwarittW, JittikoonJ, ChaikledkaewU, et al.Genetic polymorphisms of ACE1, ACE2, and TMPRSS2 associated with COVID‐19 severity: A systematic review with meta‐analysis. Rev Med Virol, 2022; 32(4):e2323.
30.
SienkoJ, MarczakI, KotowskiM, et al.Association of ACE2 gene variants with the severity of COVID-19 disease—A prospective observational study. Int J Environ Res Public Health, 2022; 19(19):12622.
31.
SinghAK, GuptaR, MisraA, et al.Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr, 2020; 14(4):283–287.
32.
SinghPP, SuravajhalaP, Basu MallickC, et al.COVID-19: Impact on linguistic and genetic isolates of India. Genes Immun, 2022; 23(1):47–50.
33.
SivaranjaneeR, KumarPS. The unfurl of the coronavirus and its thwack on humans and the environment: A review. Curr Opin Environ Sci Health, 2021; 24:100289.
34.
TekcanA, CihangirogluM, CaprazM, et al.Association of ACE ID, MTHFR C677T, and MIF-173GC variants with the clinical course of COVID-19 patients. Nucleosides Nucleotides Nucleic Acids, 2023; 42(10):782–796.
35.
VangjeliC, DickerP, TregouetD-A, et al.; MORGAM project. A polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: The MORGAM project. J Renin Angiotensin Aldosterone Syst, 2011; 12(4):504–509.
36.
XiaW, ShaoJ, GuoY, et al.Clinical and CT features in pediatric patients with COVID‐19 infection: Different points from adults. Pediatr Pulmonol, 2020; 55(5):1169–1174.
37.
YamamotoN, AriumiY, NishidaN, et al.SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. Gene, 2020; 758:144944.
38.
YanL, et al.A machine learning-based model for survival prediction in patients with severe COVID-19 infection. medRix, 2020.
39.
ZhangC, ShiL, WangF-S, et al.Liver injury in COVID-19: Management and challenges. Lancet Gastroenterol Hepatol, 2020; 5(5):428–430.
40.
ZhaoK, LiR, WuX, et al.Clinical features in 52 patients with COVID-19 who have increased leukocyte count: A retrospective analysis. Eur J Clin Microbiol Infect Dis, 2020; 39(12):2279–2287.
41.
ZhengH, CaoJJ. Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019. Am J Pathol, 2020; 190(10):2013–2017.
