ACE gene I/D polymorphism and severity of SARS-CoV-2 infection in hospitalized patients: a meta-analysis
Abstract
Background: Hypertension and type 2 diabetes increase the risk of severe SARS-CoV-2 infection. On the other hand, homozygous ACE deletion polymorphism (DD) has been associated with these two diseases and risk of acute respiratory distress syndrome. The aim of the study was to conduct a meta-analysis of the association between ACE gene I/D polymorphism (DD, II and DI) and severity of SARS-CoV-2 infection in hospitalized patients.
Material and methods: We searched PubMed, EMBASE and Google Scholar for studies published between January 2020 and April 2021. We included case-control studies evaluating the association between ACE I/D and severity of SARS-CoV-2 infection in hospitalized patients, were there was sufficient genotype or allele frequency data to calculate IRR (incidence rate ratio) and 95% confidence intervals (CIs).
Results: Five studies were included (mean age 58.5 years and 61% men), combining to a total of 786 patients. Four studies were conducted in Caucasians. Overall, patients who had homozygous co-dominance genotype DD were at 47% higher risk of severe COVID-19 compared with II or ID (IRR: 1.47; 95% CI: 1.15–1.89; p = 0.002).
Conclusions: The ACE DD genotype may confer a greater risk of severe COVID-19 in hospitalized patients. Further studies including more diverse ethnic groups are necessary to fully establish this association.
Keywords: ACE geneI/D polymorphismSARS-CoV-2COVID-19meta-analysis
References
- Kurdi M, De Mello WC, Booz GW. Working outside the system: an update on the unconventional behavior of the renin-angiotensin system components. Int J Biochem Cell Biol. 2005; 37(7): 1357–1367.
- Gemmati D, Bramanti B, Serino ML, 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. 2020; 21(10).
- Gemmati D, Tisato V. Genetic Hypothesis and Pharmacogenetics Side of Renin-Angiotensin-System in COVID-19. Genes (Basel). 2020; 11(9).
- Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2): 271–280.e8.
- Gheblawi M, Wang K, Viveiros A, et al. 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. 2020; 126(10): 1456–1474.
- Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436(7047): 112–116.
- Itoyama S, Keicho N, Quy T, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun. 2004; 323(3): 1124–1129.
- Bellone M, Calvisi SL. ACE polymorphisms and COVID-19-related mortality in Europe. J Mol Med (Berl). 2020; 98(11): 1505–1509.
- Aung ArK, Aitken T, Teh BM, et al. Angiotensin converting enzyme genotypes and mortality from COVID-19: An ecological study. J Infect. 2020; 81(6): 961–965.
- Pati A, Mahto H, Padhi S, et al. ACE deletion allele is associated with susceptibility to SARS-CoV-2 infection and mortality rate: An epidemiological study in the Asian population. Clin Chim Acta. 2020; 510: 455–458.
- Yamamoto N, Ariumi Y, Nishida N, et al. SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. Gene. 2020; 758: 144944.
- Delanghe JR, Speeckaert MM, De Buyzere ML. The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin Chim Acta. 2020; 505: 192–193.
- Moher D, Liberati A, Tetzlaff J, et al. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010; 8(5): 336–341.
- Ghasemi A, Zahediasl S. Normality tests for statistical analysis: a guide for non-statisticians. Int J Endocrinol Metab. 2012; 10(2): 486–489.
- Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006; 32(11): 1706–1712.
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3): 177–188.
- Gómez J, Albaiceta GM, García-Clemente M, et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene. 2020; 762: 145102.
- Verma S, Abbas M, Verma S, et al. Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients. Infect Genet Evol. 2021; 91: 104801.
- Calabrese C, Annunziata A, Coppola A, et al. ACE Gene I/D Polymorphism and Acute Pulmonary Embolism in COVID19 Pneumonia: A Potential Predisposing Role. Front Med (Lausanne). 2020; 7: 631148.
- Çelik SK, Genç CÇ, Piskin N, et al. ACE I/D and ACE2 receptor gene (RS2106809, RS2285666) polymorphisms is not related to the clinical course of COVID-19; a case study. Authorea Preprints. 2021.
- Gunal O, Sezer O, Ustun GU, et al. Angiotensin-converting enzyme-1 gene insertion/deletion polymorphism may be associated with COVID-19 clinical severity: a prospective cohort study. Ann Saudi Med. 2021; 41(3): 141–146.
- Matsuda A, Kishi T, Jacob A, et al. Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis. BMC Med Genet. 2012; 13: 76.
- Hu Z, Jin X, Kang Y, et al. Angiotensin-converting enzyme insertion/deletion polymorphism associated with acute respiratory distress syndrome among caucasians. J Int Med Res. 2010; 38(2): 415–422.
- Pabalan N, Tharabenjasin P, Suntornsaratoon P, et al. Ethnic and age-specific acute lung injury/acute respiratory distress syndrome risk associated with angiotensin-converting enzyme insertion/deletion polymorphisms, implications for COVID-19: A meta-analysis. Infect Genet Evol. 2021; 88: 104682.
- Liu M, Yi J, Tang W. Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst. 2021; 22(1): 1470320321995074.
- Zhou JB, Yang JK, Lu JK, et al. Angiotensin-converting enzyme gene polymorphism is associated with type 2 diabetes: a meta-analysis. Mol Biol Rep. 2010; 37(1): 67–73.
- Mengesha HG, Petrucka P, Spence C, et al. Effects of angiotensin converting enzyme gene polymorphism on hypertension in Africa: A meta-analysis and systematic review. PLoS One. 2019; 14(2): e0211054.
- Li M, Schifanella L, Larsen PA. Alu retrotransposons and COVID-19 susceptibility and morbidity. Hum Genomics. 2021; 15(1): 2.
- McFadyen JD, Stevens H, Peter K. The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications. Circ Res. 2020; 127(4): 571–587.
- Verdecchia P, Cavallini C, Spanevello A, et al. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020; 76: 14–20.
- Novelli G, Biancolella M, Mehrian-Shai R, et al. COVID-19 one year into the pandemic: from genetics and genomics to therapy, vaccination, and policy. Hum Genomics. 2021; 15(1): 27.
- Severe Covid-19 GWAS Group. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020; 383(16): 1522–1534.
- Pairo-Castineira E, Clohisey S, Klaric L, et al. GenOMICC Investigators, ISARIC4C Investigators, COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators. Genetic mechanisms of critical illness in COVID-19. Nature. 2021; 591(7848): 92–98.
- Oscanoa T, Cieza E, Lizaraso-Soto F, et al. Lack of association between angiotensin-converting enzyme (ACE) genotype and essential hypertension in Peruvian older people. Arterial Hypertension. 2020; 24(3): 115–119.
- Bonfim-Silva R, Guimarães LO, Souza Santos J, et al. Case-control association study of polymorphisms in the angiotensinogen and angiotensin-converting enzyme genes and coronary artery disease and systemic artery hypertension in African-Brazilians and Caucasian-Brazilians. J Genet. 2016; 95(1): 63–69.