SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease

Abstract

COVID-19 and the renin-angiotensin system (RAS) are linked by angiotensin-converting enzyme 2 (ACE2), a key enzyme in RAS that has been validated as a SARS-CoV-2 receptor. Functional ACE1/ACE2 gene polymorphisms may lead to the imbalance between ACE/ACE2 ratio and thus generating RAS imbalance that is associated with higher degrees of lung damage in ARDS that may contribute to the COVID-19 infection outcome. Herein, we investigated the role of RAS gene polymorphisms, ACE1 (A2350G) and ACE2 (G8790A) as risk predictors for susceptibility and severity of COVID-19 infection. A total of 129 included: negative controls without a history of COVID-19 infection (n = 50), positive controls with a history of COVID-19 infection who were not hospitalized (n = 35), and patients with severe COVID-19 infection who were hospitalized in the intensive care unit (n = 44). rs4343 of ACE and rs2285666 of ACE2 were genotyped using PCR–RFLP method. Our results indicated that susceptibility to COVID-19 infection was associated with age, GG genotype of A2350G (Pa = 0.01; OR 4.7; 95% CI 1.4–15.1 and Pc = 0.040; OR 2.5; 95% CI 1.05–6.3) and GG genotype of G8790A (Pa = 0.044; OR 6.17; 95% CI 1.05–35.71 and Pc = 0.0001; OR 5.5; 95% CI 2.4–12.4). The G allele of A2350G (Pa = 0.21; OR 1.74; 95% CI 0.73–4.17 and Pc = 0.007; OR 2.1; 95% CI 1.2–3.5) and G allele of G8790A (Pa = 0.002; OR 4.26; 95% CI 1.7–10.65 and Pc = 0.0001; OR 4.7; 95% CI 2.4–9.2) were more frequent in ICU-admitted patients and positive control group. Also lung involvement due to COVID-19 infection was associated with age and the comorbidities such as diabetes. In conclusion, our findings support the association between the wild genotype (GG) of ACE2 and homozygote genotype (GG) of ACE1 and sensitivity to COVID-19 infection, but not its severity. However, confirmation of this hypothesis requires further studies with more participants.

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 ...…”

Global distribution of ACE1 (rs4646994) and ACE2 (rs2285666) polymorphisms associated with COVID-19: A systematic review and meta-analysis

“…According to the defined criteria, titles, abstracts, and full-text of articles were reviewed by two separate authors. In this meta-analysis, characteristics such as first author, publication year, country, allelic/genotype distribution of rs4646994, and allelic/genotype distribution of rs2285666 were considered as eligible criteria ( Table 1 ) [ [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] ].…”

Inflammasome Genetic Variants Are Associated with Protection to Clinical Severity of COVID-19 among Patients from Rio de Janeiro, Brazil

“…BioMed Research International However, data exploring the role of inflammasomes in SARS-CoV-2 infection remain scarce. Genetic factors contributing to the outcome of SARS-CoV-2 infection remain unclear; however, variants in specific sites of the ACE2 and TMPRSS2 genes, as well as the ABO locus, have already been considered genetic risk factors for COVID-19 outcomes [38][39][40][41][42]. Currently, new candidate genes have been described in the literature as influencing susceptibility to COVID-19.…”