Association of pro-inflammatory and anti-inflammatory cytokine polymorphisms with COVID-19 severity in unvaccinated patients

Laura Edith Martínez-Gómez¹Carla Isabel Oropeza-Vélez²Maylin Almonte-Becerril³Leslie Chavez-Galan⁴Carlos Martinez Armenta¹Patricia Vidal-Vazquez⁵Juan Pablo Ramirez Hinojosa⁵Paola Vázquez-Cárdenas⁵Diana Gómez-Martín⁶Gilberto Vargas Alarcón⁷José Manuel Rodríguez-Pérez⁷Lucero A. Ramón-Luing⁴Julio Flores González⁴José G Carrasco⁸IVETTE CRUZ BAUTISTA⁶Monica Mata⁹Gustavo Jesus Vazquez-Zapien⁹Adriana Martínez Cuazitl⁹Nancy Parra-Torres³Felipe De Jesús Martinez Ruiz¹⁰Dulce M Zayago-Angeles¹⁰Ma Luisa Ordoñez-Sánchez⁶Yayoi Segura-Kato⁶Carlos Suarez-Ahedo¹¹Jessel Olea-Torres¹¹Brígida Herrera-López¹¹Carlos Pineda¹¹Gabriela Angélica Martínez-Nava¹¹Alberto López-Reyes^11*

• ¹National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Tlalpan, Mexico
• ²Servicio de Medicina Interna de Hospital, Petroleos Mexicanos, Mexico City, Mexico
• ³Universidad de la Salud, Mexico City, Mexico
• ⁴Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
• ⁵Hospital General Dr Manuel Gea Gonzalez, Mexico City, Mexico
• ⁶Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
• ⁷Instituto Nacional de Cardiologia Ignacio Chavez, State of Mexico, Mexico
• ⁸Petroleos Mexicanos, Mexico City, Mexico
• ⁹Laboratorio de Biología Celular y Tisular, Laboratorio de Embriología, Escuela Medico Militar, Mexico City, Mexico
• ¹⁰Nuevo Hospital General Delegación Regional Sur de la Ciudad de México, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico City, Mexico
• ¹¹Instituto Nacional de Rehabilitacion Luis Guillermo Ibarra Ibarra, Mexico City, Mexico

Background: Cytokines and chemokines are essential for establishing an appropriate immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Variations in the genes encoding cytokines and chemokines strongly influence the immune response to pathogenic challenges and disease outcomes. This study was conducted to investigate the associations between polymorphisms in the TNF-α, IL-6, IL-8, IL-10, and CCL5 genes and COVID-19 severity.We performed a cross-sectional study with a total of 627 unvaccinated COVID-19 patients were classified according to WHO disease severity. We evaluated the levels of IFN-α, IFN-γ, TNF-α, IL-1Ra, IL-2, IL-6, IL-7, IL-10, CCL2, CCL3, CXCL8, CXCL10 and GCSF in the serum and compared them among COVID-19 severity groups by Kruskal-Wallis test and stratified by polymorphism alleles. A logistic regression was performed to determine the association of the polymorphism and COVID-19 severity.Results: This study revealed a significant increase in IL-2, IL-6 and CCL-2 levels in the deceased group. However, the IL-10 levels were higher in the moderate group than in the mild group. Logistic regression analysis revealed that five polymorphisms were associated with a higher risk of severe COVID-19: the TNF-α (rs1800610) A allele (OR=1.50; 95% CI: 1.01-2.24); the IL-6 (rs1800796) C allele (OR=1.64; 95% CI: 1.05-2.57); the IL-10 (rs1800871) T allele (OR=1.94; 95% CI: 1.24-3.04) and (rs1800872) A allele (OR=1.87; 95% CI: 1.21-2.89); and the CCL5 (rs3817656) G allele (OR= 1.64; 95% CI: 1.02-2.65).Patients infected with SARS-CoV-2 who have the TNFα gene variant (rs1800629) are protected from developing COVID-19 moderate and severe outcomes, as well as from presenting low concentrations of some pro-inflammatory cytokines and chemokines. However, carriers of the IL-10 (rs1800872, rs1800871) and CCL-5 (rs2107538) gene variants were associated with patients who died from COVID-19. Of these, only the minor allele of CCL-5 was primarily associated with increased chemokines levels, as well as with some cytokines considered hallmarks of the cytokine storm.