GSTO1, GSTO2 and ACE2 Polymorphisms Modify Susceptibility to Developing COVID-19

Abstract

Based on the close relationship between dysregulation of redox homeostasis and immune response in SARS-CoV-2 infection, we proposed a possible modifying role of ACE2 and glutathione transferase omega (GSTO) polymorphisms in the individual propensity towards the development of clinical manifestations in COVID-19. The distribution of polymorphisms in ACE2 (rs4646116), GSTO1 (rs4925) and GSTO2 (rs156697) were assessed in 255 COVID-19 patients and 236 matched healthy individuals, emphasizing their individual and haplotype effects on disease development and severity. Polymorphisms were determined by the appropriate qPCR method. The data obtained showed that individuals carrying variant GSTO1*AA and variant GSTO2*GG genotypes exhibit higher odds of COVID-19 development, contrary to ones carrying referent alleles (p = 0.044, p = 0.002, respectively). These findings are confirmed by haplotype analysis. Carriers of H2 haplotype, comprising GSTO1*A and GSTO2*G variant alleles were at 2-fold increased risk of COVID-19 development (p = 0.002). Although ACE2 (rs4646116) polymorphism did not exhibit a statistically significant effect on COVID-19 risk (p = 0.100), the risk of COVID-19 development gradually increased with the presence of each additional risk-associated genotype. Further studies are needed to clarify the specific roles of glutathione transferases omega in innate immune response and vitamin C homeostasis once the SARS-CoV-2 infection is initiated in the host cell.

Genetic analysis of ACE2 peptidase domain in SARS-CoV-2-positive and SARS-CoV-2-negative individuals from Pakistan

“…This variant has been reported in gnomAD with MAF of 0.388% and 0.131% in the general population and South Asians, respectively. In our study the solitary SARS-CoV-2-positive patient carrying p.Lys26Arg variant showed mild COVID-19 disease symptoms in agreement with previous reports from Serbia [31] and Germany [17]. Collectively, these ndings suggest that the p.Lys26Arg variant may neither be associated with increased SARS-CoV-2 infection nor depict a protective effect.…”

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…Several studies pointed out that GSH and the enzymes associated with the GSH pathway are involved in SARS-CoV-2 infection and COVID-19 disease. Recent studies demonstrated that individuals with glutathione transferase omega polymorphisms, genotype variants GSTO1*AA (rs4925) and GSTO2*GG (rs156697), showed significant propensity towards development of clinical manifestations in COVID-19 supporting the significance of these enzymes in the regulation of redox homeostasis and immune response, especially NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation ( Zhao and Zhao, 2020 ; Djukic et al, 2022 ). Combined glutathione S-transferase (GST)P1 (rs1138272 and rs1695) and GSTM3 genotypes showed cumulative risk regarding both occurrence and severity of COVID-19 ( Coric et al, 2021 ).…”

Genetic analysis of ACE2 peptidase domain in SARS-CoV-2-positive and SARS-CoV-2-negative individuals from Pakistan

“…The relevance of germline ACE2 variants as a screening target for the risk assessment of SARS-CoV-2 infection is of interest. Most of such studies have investigated the association between ACE2 variants and SARS-CoV-2 infection or COVID-19 disease severity using bioinformatics approaches while utilizing the frequencies of ACE2 genetic variants from public databases [10,14,[24][25][26][27][28] 16,18,20,29,30]. Variants in most of these residues are absent or present with a low frequency (MAF < 0.0006) in the general population (gnomAD database).…”