The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes
Laura Edith Martínez-Gómez, Carlos Martinez-Armenta, Teresa Tusie-Luna, Paola Vázquez-Cárdenas, Rosa P Vidal-Vázquez, Juan P Ramírez-Hinojosa, Diana Gómez-Martín, Gilberto Vargas-Alarcón, Rosalinda Posadas-Sánchez, José Manuel Fragoso, Aurora De La Peña, José Manuel Rodríguez-Pérez, Mónica M Mata-Miranda, Gustavo J Vázquez-Zapién, Adriana Martínez-Cuazitl, Felipe De J Martínez-Ruiz, Dulce M Zayago-Angeles, Luis Ramos-Tavera, Alberto Méndez-Aguilera, María Del C Camacho-Rea, María L Ordoñez-Sánchez, Yayoi Segura-Kato, Carlos Suarez-Ahedo, Jessel Olea-Torres, Brígida Herrera-López, Carlos Pineda, Gabriela A Martínez-Nava, Alberto López-Reyes
Frontiers in Immunology, doi:10.3389/fimmu.2024.1335963
Introduction: Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes. Methods: To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity). Results: According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667
Ethics statement The study was approved by the ethics committee of (INR-LGII: 17/20). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
Author contributions
LM
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1335963/ full#supplementary-material SUPPLEMENTARY 1 TMPRSS2 and SERPINE1 polymorphism allelic and genotype frequencies in the population study.
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'abstract': '<jats:sec><jats:title>Introduction</jats:title><jats:p>Serine proteases play a critical role '
'during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 '
'(<jats:italic>TMPRSS2</jats:italic>) and serpine family E member 1 '
'(<jats:italic>SERPINE1</jats:italic>) could help to elucidate the contribution of variability '
'to COVID-19 outcomes.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To '
'evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we '
'performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were '
'enrolled. <jats:italic>TMPRSS2</jats:italic> (rs2070788, rs75603675, rs12329760) and '
'<jats:italic>SERPINE1</jats:italic> (rs2227631, rs2227667, rs2070682, rs2227692) were '
'genotyped using the Open Array Platform. The association of polymorphisms with disease '
'outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, '
'hypertension, type 2 diabetes, and '
'obesity).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>According to '
'our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; '
'<jats:italic>p</jats:italic>=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = '
'0.38-0.91; <jats:italic>p</jats:italic>=0.02) of <jats:italic>SERPINE1</jats:italic> played a '
'protective role against disease. However, the rs2227692 T allele and TT genotype '
'<jats:italic>SERPINE1</jats:italic> (OR=1.45; 95% CI = 1.11-1.91; '
'<jats:italic>p</jats:italic>=0.006; OR=2.08; 95% CI = 1.22-3.57; '
'<jats:italic>p</jats:italic>=0.007; respectively) were associated with a decreased risk of '
'death. Similarly, the rs75603675 AA genotype <jats:italic>TMPRSS2</jats:italic> had an OR of '
'1.97 (95% CI = 1.07-3.6; <jats:italic>p</jats:italic>=0.03) for deceased patients. Finally, '
'the rs2227692 T allele <jats:italic>SERPINE1</jats:italic> was associated with increased '
'D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; '
'<jats:italic>p</jats:italic>=0.02).</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Our '
'data suggest that the rs75603675 <jats:italic>TMPRSS2</jats:italic> and rs2227692 '
'<jats:italic>SERPINE1</jats:italic> polymorphisms are associated with a poor outcome. '
'Additionally, rs2227692 <jats:italic>SERPINE1</jats:italic> could participate in '
'hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could '
'contribute to the identification of new pharmacological targets and treatment strategies to '
'block the inhibition of TMPRSS2 entry into SARS-CoV-2.</jats:p></jats:sec>',
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