AUTHOR=Martínez-Gómez Laura Edith , Martinez-Armenta Carlos , Tusie-Luna Teresa , Vázquez-Cárdenas Paola , Vidal-Vázquez Rosa P. , Ramírez-Hinojosa Juan P. , Gómez-Martín Diana , Vargas-Alarcón Gilberto , Posadas-Sánchez Rosalinda , Fragoso José Manuel , de la Peña Aurora , Rodríguez-Pérez José Manuel , Mata-Miranda Mónica M. , Vázquez-Zapién Gustavo J. , Martínez-Cuazitl Adriana , Martínez-Ruiz Felipe de J. , Zayago-Angeles Dulce M. , Ramos-Tavera Luis , Méndez-Aguilera Alberto , Camacho-Rea María del C. , Ordoñez-Sánchez María L. , Segura-Kato Yayoi , Suarez-Ahedo Carlos , Olea-Torres Jessel , Herrera-López Brígida , Pineda Carlos , Martínez-Nava Gabriela A. , López-Reyes Alberto 

TITLE=The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1335963

DOI=10.3389/fimmu.2024.1335963

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (<italic>TMPRSS2</italic>) and serpine family E member 1 (<italic>SERPINE1</italic>) could help to elucidate the contribution of variability to COVID-19 outcomes.</p></sec><sec><title>Methods</title><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. <italic>TMPRSS2</italic> (rs2070788, rs75603675, rs12329760) and <italic>SERPINE1</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).</p></sec><sec><title>Results</title><p>According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; <italic>p</italic>=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; <italic>p</italic>=0.02) of <italic>SERPINE1</italic> played a protective role against disease. However, the rs2227692 T allele and TT genotype <italic>SERPINE1</italic> (OR=1.45; 95% CI = 1.11-1.91; <italic>p</italic>=0.006; OR=2.08; 95% CI = 1.22-3.57; <italic>p</italic>=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype <italic>TMPRSS2</italic> had an OR of 1.97 (95% CI = 1.07-3.6; <italic>p</italic>=0.03) for deceased patients. Finally, the rs2227692 T allele <italic>SERPINE1</italic> was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; <italic>p</italic>=0.02).</p></sec><sec><title>Discussion</title><p>Our data suggest that the rs75603675 <italic>TMPRSS2</italic> and rs2227692 <italic>SERPINE1</italic> polymorphisms are associated with a poor outcome. Additionally, rs2227692 <italic>SERPINE1</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.</p></sec>