GSTP1 and GSTM3 Variant Alleles Affect Susceptibility and Severity of COVID-19

Abstract

Based on the premise that oxidative stress plays an important role in severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, we speculated that variations in the antioxidant activities of different members of the glutathione S-transferase family of enzymes might modulate individual susceptibility towards development of clinical manifestations in COVID-19. The distribution of polymorphisms in cytosolic glutathione S-transferases GSTA1, GSTM1, GSTM3, GSTP1 (rs1695 and rs1138272), and GSTT1 were assessed in 207 COVID-19 patients and 252 matched healthy individuals, emphasizing their individual and cumulative effect in disease development and severity. GST polymorphisms were determined by appropriate PCR methods. Among six GST polymorphisms analyzed in this study, GSTP1 rs1695 and GSTM3 were found to be associated with COVID-19. Indeed, the data obtained showed that individuals carrying variant GSTP1-Val allele exhibit lower odds of COVID-19 development (p = 0.002), contrary to carriers of variant GSTM3-CC genotype which have higher odds for COVID-19 (p = 0.024). Moreover, combined GSTP1 (rs1138272 and rs1695) and GSTM3 genotype exhibited cumulative risk regarding both COVID-19 occurrence and COVID-19 severity (p = 0.001 and p = 0.025, respectively). Further studies are needed to clarify the exact roles of specific glutathione S-transferases once the SARS-CoV-2 infection is initiated in the host cell.

SOD2 rs4880 and GPX1 rs1050450 polymorphisms do not confer risk of COVID-19, but influence inflammation or coagulation parameters in Serbian cohort

“…Herein, we further substantiated results by haplotype analysis of GSTP1 genotypes and found that carriers of H2 haplotype (presence of GSTP1 rs1695 variant allele and GSTP1 rs1138272 referent allele) exhibited the lowest risk of susceptibility of COVID-19. In view of the fact that GSTP1 is highly expressed in lung tissue and might even be considered as predominant GST in the lungs, this result is biologically plausible [ 11 , 35–38 ]. As previously discussed, GSTP1 might modulate the susceptibility to various pulmonary diseases [ 11 ].…”

“…In view of the fact that GSTP1 is highly expressed in lung tissue and might even be considered as predominant GST in the lungs, this result is biologically plausible [ 11 , 35–38 ]. As previously discussed, GSTP1 might modulate the susceptibility to various pulmonary diseases [ 11 ]. The question arrases why examined polymorphisms of immediate and first line antioxidant enzymes SOD2, GPX1, and GPX3 in our study did not have association either with susceptibility or severity of COVID-19, despite the fact that redox homeostasis misbalance is one of the significant underlying mechanisms in COVID-19 disease.…”

“…As mentioned before, our latest findings showed that both genetic variants in GSTP1 , Ile105Val (rs1695), and Ala114Val (rs1138272) are associated with susceptibility and severity of COVID-19 [ 11 ]. Herein, we further substantiated results by haplotype analysis of GSTP1 genotypes and found that carriers of H2 haplotype (presence of GSTP1 rs1695 variant allele and GSTP1 rs1138272 referent allele) exhibited the lowest risk of susceptibility of COVID-19.…”

“…In COVID-19, recent findings pointed to the importance of polymorphisms in glutathione transferase (GST) superfamily of proteins that belong to the first line of enzymatic antioxidant defense. Concisely, COVID-19 patients with GSTT1-null genotype exhibit higher mortality and according to our latest results, GSTP1 (rs1695 and rs1138272) polymorphisms influence susceptibility and severity of COVID-19 [ 8 , 11 ]. Genes encoding both regulatory and catalytic antioxidant proteins exhibit relatively frequent genetic polymorphisms, resulting in complete lack, or altered enzyme activity.…”

The association of glutathione transferase omega polymorphisms with laboratory inflammatory parameters in COVID-19

“…Considering diverse variations in severity, duration and outcomes of coronavirus disease 2019 (COVID-19), defining a genetic predisposition, along with clinical and environmental factors, might be an important step in improving the diagnosis and treatment of high-risk individuals. Due to the established role of oxidative distress in the pathophysiology of COVID-19, it has been proposed that inter-individual differences in patients' clinical manifestations might also be affected by variations in genes encoding detoxifying and antioxidant enzymes, glutathione transferases (GSTs) (1). GSTs are a superfamily of enzymes that catalyze the conjugation of glutathione (GSH) to a wide range of chemical carcinogens, drugs and oxidative stress products.…”