The Role of ACE, ACE2, and AGTR2 Polymorphisms in COVID-19 Severity and the Presence of COVID-19-Related Retinopathy

Abstract

The proposed SARS-CoV-2-induced dysregulation of the renin-angiotensin-aldosterone (RAAS) system results in endothelial dysfunction and microvascular thrombosis. The retinal plexuses contain terminal vessels without anastomotic connections, making the retina especially susceptible to ischemia. This study aimed to determine the role of selected polymorphisms of genes in the RAAS pathway in COVID-19 severity and their association with the presence of COVID-19 retinopathy. 69 hospitalized patients in the acute phase of COVID-19 without known systemic comorbidities and 96 healthy controls were enrolled in this prospective cross-sectional study. The retina was assessed with fundus photography using a Topcon DRI OCT Triton (Topcon Corp., Tokyo, Japan) in the COVID-19 unit. Genotyping of selected polymorphisms in the genes for ACE (rs4646994), ACE2 (rs2285666), and AGTR2 (rs1403543) was performed. The COVID-19 group was divided into mild (n = 12) and severe (n = 57), and then further divided according to the presence of COVID-19 retinopathy (Yes, n = 50; No, n = 19). The presence of the AGTR2 rs1403543-AA genotype was associated with a 3.8-fold increased risk of COVID-19 retinopathy (p = 0.05). The genotype frequencies of selected gene polymorphisms were not significantly associated with either the presence of COVID-19 or its severity. This is the first study demonstrating a borderline association of the AGTR2 rs1403543-AA genotype with COVID-19 retinopathy in males; hence, the AGTR2 rs 1403543 A allele might represent a genetic risk factor for COVID-19 retinopathy in males.

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] ].…”

Causal associations and shared genetics between hypertension and COVID‐19

“…Several previous single-gene association studies and systematic reviews implicated common polymorphisms within the RAAS loci in COVID-19-associated phenotypes. 46,47 Nevertheless, our FUMA-guided gene overlap analysis did not uncover any loci encoding the proteins of RAAS as shared between hypertension and hospitalized COVID-19.…”

The Comparison of Retinal Microvascular Findings in Acute COVID-19 and 1-Year after Hospital Discharge Assessed with Multimodal Imaging—A Prospective Longitudinal Cohort Study

“…It is noteworthy that ACE, ACE2, and AGTR2 polymorphisms have also been associated with hypertension, diabetes, coronary artery disease, and stroke [ 16 , 17 , 18 , 19 , 20 , 21 ], which complicates the risk estimation, as those comborbities alone are associated with an increased risk of COVID-19. Nevertheless, our previous study, focusing on patients without known comorbidities, showed an increased risk of COVID-19 retinopathy in males with the AGTR2-AA genotype of the rs1403543 polymorphism [ 34 ].…”