Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19
María Fernanda López-Bielma,
Ramcés Falfán-Valencia,
Aurelio Fierro-Piña,
Edgar Abarca-Rojano,
Elizabeth Córdoba-Lanus,
Ingrid Fricke-Galindo,
Priscila Romero-Villaseñor,
Ivette Buendía-Roldán,
Leslie Chávez-Galán,
María Esther Jaime-Capetillo,
Gloria Pérez-Rubio
Affiliations
María Fernanda López-Bielma
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico; Sección de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico
Ramcés Falfán-Valencia
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
Aurelio Fierro-Piña
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
Edgar Abarca-Rojano
Sección de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico
Elizabeth Córdoba-Lanus
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296, San Cristóbal de La Laguna, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
Ingrid Fricke-Galindo
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
Priscila Romero-Villaseñor
Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
Ivette Buendía-Roldán
Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
Leslie Chávez-Galán
Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico
María Esther Jaime-Capetillo
Clinical Laboratory Service, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, 14080, Mexico
Gloria Pérez-Rubio
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, 14080, Mexico; Corresponding author.
Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes.
