Angiotensin-Converting Enzyme Genotype–Specific Immune Response Contributes to the Susceptibility of COVID-19: A Nested Case–Control Study

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has resulted in a global pandemic.Methodology: We used a two-step polymerase chain reaction to detect the ACE genotype and ELISA kits to detect the cytokine factor. We also used proteomics to identify the immune pathway related to the ACE protein expression.Result: In this study, we found that the angiotensin-converting enzyme (ACE) deletion polymorphism was associated with the susceptibility to COVID-19 in a risk-dependent manner among the Chinese population. D/D genotype distributions were higher in the COVID-19 disease group than in the control group (D/D odds ratio is 3.87 for mild (p value < 0.0001), 2.59 for moderate (p value = 0.0002), and 4.05 for severe symptoms (p value < 0.0001), logic regression analysis. Moreover, genotype-specific cytokine storms and immune responses were found enriched in patients with the ACE deletion polymorphism, suggesting the contribution to the susceptibility to COVID-19. Finally, we identified the immune pathway such as the complement system related to the ACE protein expression of patients by lung and plasma proteomics.Conclusion: Our results demonstrated that it is very important to consider gene polymorphisms in the population to discover a host-based COVID-19 vaccine and drug design for preventive and precision medicine.

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

“…Among the studies included in the susceptibility analysis, the control groups of the following studies did not follow Hardy-Weinberg equilibrium (HWE): ACE1 I/D rs4646994/rs1799752 ( Aladag et al, 2021 Sep , Mir et al, 2021 Oct 27 ); ACE2 rs2285666 ( Möhlendick et al, 2021 Oct 1 ); CCR5 rs333 ( Gómez et al, 2020 ); TMPRSS2 rs12329760 ( Taha et al, 2022 Mar 1 ) and TNFA rs1800629 ( Rokni et al, 2022 Apr , Heidari Nia et al, 2022 ). In the severity analysis, HWE did not exist in the control groups of the following studies: ACE1 I/D rs4646994/rs1799752 ( Gong et al, 2021 , Gunal et al, 2021 Jun , Akbari et al, 2022 Feb , Möhlendick et al, 2021 Oct 1 , Kouhpayeh et al, 2021 Nov 17 ); ACE2 rs2285666 ( Martínez-Gómez et al, 2022 Feb , Möhlendick et al, 2021 Oct 1 ); ACE2 rs2106809 ( Cafiero et al, 2021 May , Sabater Molina et al, 2022 ); ACE2 rs2074192 ( Martínez-Gómez et al, 2022 Feb , Sabater Molina et al, 2022 , Wang et al, 2022 Jan ) , IFITM3 rs12252 ( Abbas et al, 2021 Jun 12 ); TMPRSS2 rs12329760 ( Ravikanth et al, 2021 Sep ); TNFA rs1800629 ( Rokni et al, 2022 Apr ) and VDR rs731236 ( Russo et al, 2021 Jun 8 , Abdollahzadeh et al, 2021 Dec ).…”

“…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] ].…”

Impaired Humoral Immunity Identified in Inactivated SARS-CoV-2 Vaccine Recipients without Anti-Spike RBD Antibodies

“…Angiotensin-converting enzyme (ACE) polymorphism has been associated with various heart-related and other diseases such as atherosclerosis ( 12 ), myocardial infarction ( 13 ), ischemic stroke ( 14 ), and hypertension ( 15 ). ACE deletion polymorphism was recently reported to be associated with susceptibility to COVID-19 in a risk-dependent manner among the Chinese population ( 16 ). We therefore examined the levels of anti-Spike RBD antibodies in subjects with a family history of cardiovascular disease and found no difference with those in subjects with no family history of cardiovascular disease ( P = 0.482; Fig.…”