The Role of Angiotensin Converting Enzyme 1 Insertion/Deletion Genetic Polymorphism in the Risk and Severity of COVID-19 Infection

Abstract

Background: Individuals infected with the COVID-19 virus present with different symptoms of varying severity. In addition, not all individuals are infected despite exposure. Risk factors such as age, sex, and comorbidities play a major role in this variability; however, genetics may also be important in driving the differences in the incidence and prognosis of the disease. An Insertion/Deletion (I/D) polymorphism in the ACE1 gene (rs1799752) may explain these genetic differences. The aims of this study were to determine the potential role of ACE1 I/D genetic polymorphism in the risk of contracting COVID-19 as well as predicting the severity of COVID-19 infection.Methods: Three-hundred and eighty-seven non-related Lebanese subjects, 155 controls and 232 cases, who presented to the American University of Beirut Medical Center (AUBMC) for COVID-19 PCR testing were recruited. Clinical data were collected via filling a questionnaire and accessing the medical records. Peripheral blood was withdrawn for DNA isolation, and genotyping performed with standard PCR followed by band visualization on agarose gel.Results: In our study population, previously described risk factors such as gender, age, and comorbidities were associated with increase in disease susceptibility and severity. ACE1 I was the least common allele, and there was a positive association between ACE1 I and the risk of contracting the COVID-19 disease. More specifically, the frequency of II genotype was significantly higher among cases when compared to controls (P = 0.035) with individuals with the II genotype having greater risk for contracting the COVID-19 disease: OR = 2.074, P = 0.048 in the multivariate analysis. As for disease severity, the DD genotype and D allele were associated with increased risk for developing severe symptoms (OR = 2.845, P = 0.026 and OR = 2.359, P = 0.014, respectively), and the DD genotype with necessitating hospitalization (OR = 2.307, P = 0.042). In parallel, D allele carriers showed a significantly increased risk for developing hypoxia: OR = 4.374, P = 0.045.Conclusion: We found a positive association between ACE1 I and the risk of contracting the COVID-19 disease, and between ACE1 D and a worse outcome of the COVID-19 infection. Therefore, genotyping for ACE1 I/D polymorphism could be used to assess risk and predict severity for better prognosis and management of the disease.

Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity

“…The studies for susceptibility analysis included: ACE1 I/D rs4646994/rs1799752 ( Annunziata et al, 2021 Aug 20 , Gong et al, 2021 , Aladag et al, 2021 Sep , Papadopoulou et al, 2022 Mar , Akbari et al, 2022 Feb , Calabrese et al, 2021 Jan , Saad et al, 2021 Dec , Möhlendick et al, 2021 Oct 1 , Gómez et al, 2020 Dec , Hubacek et al, 2021 Aug , Kouhpayeh et al, 2021 Nov 17 , Mahmood et al, 2022 Feb , Mir et al, 2021 Oct 27 ); ACE2 rs2285666 ( Möhlendick et al, 2021 Oct 1 , Alimoradi et al, 2022 Mar 19 , Gómez et al, 2020 Dec , Mahmood et al, 2022 Feb ); APOE rs429358 ( Kuo et al, 2020 May 26 , Al-Jaf et al, 2021 Nov , Hilser et al, 2021 Jan ); CCR5 rs333 ( Cuesta-Llavona et al, 2021 Sep , Bernas et al, 2021 Apr , Gómez et al, 2020 ); IFITM3 rs12252 ( Abbas et al, 2021 Jun 12 , Schönfelder et al, 2021 Jun , Gómez et al, 2021 Jan ); TMPRSS2 rs12329760 ( Taha et al, 2022 Mar 1 , Andolfo et al, 2021 , Schönfelder et al, 2021 Apr , Wulandari et al, 2021 ), and TNFA rs1800629 ( Rokni et al, 2022 Apr , Saleh et al, 2020 Nov , Heidari Nia et al, 2022 ). Severity-wise analysis was performed for ACE1 I/D rs4646994/rs1799752 ( Karakaş Çelik et al, 2021 Oct , Gong et al, 2021 , Gunal et al, 2021 Jun , Martínez-Gómez et al, 2022 Feb , Baştuğ et al, 2021 Dec 8 , Akbari et al, 2022 Feb , Saad et al, 2021 Dec , Möhlendick et al, 2021 Oct 1 , Cafiero et al, 2021 May , Gómez et al, 2020 Dec , Hubacek et al, 2021 Aug , Kouhpayeh et al, 2021 Nov 17 , Mahmood et al, 2022 Feb , Mir et al, 2021 Oct 27 ...…”

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: a systematic review and meta-analysis

“…Basic characteristics of the remaining 29 studies (Abdollahzadeh et al, 2021[ 1 ]; Aladag et al, 2021[ 4 ]; Al-Anouti et al, 2021[ 5 ]; Alghamdi et al, 2021[ 6 ]; Akbari et al, 2022[ 2 ]; Akin et al, 2022[ 3 ]; Apaydin et al, 2022[ 7 ]; Cafiero et al, 2021[ 10 ]; Karakaş Çelik et al, 2021[ 26 ]; Cuesta-Llavona et al, 2021[ 13 ]; Gómez et al, 2020[ 20 ]; Gómez et al, 2021[ 19 ]; Gunal et al, 2021[ 21 ]; Hubacek et al, 2021[ 23 ]; Íñiguez et al, 2021[ 24 ]; Kotur et al, 2021[ 27 ]; Kouhpayeh et al, 2021[ 28 ]; Mir et al, 2021[ 33 ]; Möhlendick et al, 2021[ 34 ]; Monticelli et al, 2021[ 35 ]; Novelli et al, 2020[ 36 ]; Peralta et al, 2021[ 39 ]; Ravikanth et al, 2021[ 43 ]; Saad et al, 2021[ 45 ]; Schönfelder et al, 2021[ 49 ][ 48 ]; Verma et al, 2021[ 53 ]; Wang et al, 2022[ 55 ]; Wulandari et al, 2021[ 57 ]; Zhang et al, 2020[ 59 ]), with a total number of 8247 SARS-CoV-2-positive participants, included in qualitative data synthesis, are given in Table 1 (Tab. 1) (References in Table 1: Abdollahzadeh et al, 2021[ 1 ]; Akbari et al, 2022[ 2 ]; Akin et al, 2022[ 3 ]; Aladag et al, 2021[ 4 ]; Al-Anouti et al, 2021[ 5 ]; Alghamdi et al, 2021[ 6 ]; Apaydin et al, 2022[ 7 ]; Cafiero et al, 2021[ 10 ]; Cuesta-Llavona et al, 2021[ 13 ]; Gómez et al , 2020[ 20 ], 2021[ 19 ]; Gunal et al, 2021[ 21 ]; Hubacek et al, 2021[ 23 ]; Íñiguez et al, 2021[ 24 ]; Karakaş Çelik et al, 2021[ 26 ]; Kotur et al, 2021[ 27 ]; Kouhpayeh et al, 2021;[ 28 ] Mir et al, 2021[ 33 ]; Möhlendick et al, 2021[ 34 ]; Monticelli et al, 2021[ …”

“…2) , Figure 2 (Fig. 2) ; References in Figure 2: Karakaş Çelik et al, 2021[ 26 ]; Möhlendick et al, 2021[ 34 ]; Saad et al, 2021[ 45 ]). Furthermore, among patients hospitalized with severe or moderate illness, minor allele I was found to associate with lower COVID-19 severity (Table 2 (Tab.…”

“…2) , Figure 3 (Fig. 3) ; References in Figure 3: Aladag et al, 2021[ 4 ]; Gómez et al , 2020[ 20 ]; Karakaş Çelik et al, 2021[ 26 ]; Kouhpayeh et al, 2021[ 28 ]; Möhlendick et al, 2021[ 34 ]; Saad et al, 2021[ 45 ]; Verma et al, 2021[ 53 ]). Contrary to these results, minor allele I was shown to confer an increased risk of lethal outcome in COVID-19 patients.…”

Association Between the LZTFL1 rs11385942 Polymorphism and COVID-19 Severity in Colombian Population

“…Angiotensin I converting enzyme and angiotensin converting enzyme 2, coded by the genes ACE and ACE2 , respectively, are critical regulators of this pathway and may also contribute to multiple organ injuries in COVID-19. In lung vascular endothelium, ACE catalyzes Angiotensin I conversion into Angiotensin II, an active peptide that promotes vasoconstriction, inflammation and thrombosis ( 15 ). Conversely, ACE2 converts Angiotensin II into angiotensin-( 1 – 7 ), molecules that counteract the effects of Angiotensin II, including vasodilatation and vascular protection ( 16 ).…”