Genetic signature detected in T cell receptors from patients with severe COVID-19
Manuel Corpas,
Carmen de Mendoza,
Víctor Moreno-Torres,
Ilduara Pintos,
Pedro Seoane,
James R. Perkins,
Juan A.G. Ranea,
Segun Fatumo,
Tamas Korcsmaros,
José Manuel Martín-Villa,
Pablo Barreiro,
Octavio Corral,
Vicente Soriano
Affiliations
Manuel Corpas
School of Life Sciences, University of Westminster, London, UK; Cambridge Precision Medicine Limited, ideaSpace, University of Cambridge Biomedical Innovation Hub, Cambridge, UK; UNIR Health Sciences School & Medical Center, Madrid, Spain; Institute of Continuing Education, University of Cambridge, Cambridge, UK; Corresponding author
Carmen de Mendoza
Puerta de Hierro University Hospital & Research Institute, Majadahonda, Spain
Víctor Moreno-Torres
UNIR Health Sciences School & Medical Center, Madrid, Spain; Puerta de Hierro University Hospital & Research Institute, Majadahonda, Spain
Ilduara Pintos
Puerta de Hierro University Hospital & Research Institute, Majadahonda, Spain
Pedro Seoane
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
James R. Perkins
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; The Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain
Juan A.G. Ranea
Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; The Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain; Spanish National Bioinformatics Institute (INB/ELIXIR-ES), Madrid, Spain
Segun Fatumo
The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM, Entebbe, Uganda; London School of Hygiene and Tropical Medicine, London, UK; H3Africa Bioinformatics Network (H3ABioNet) Node, Centre for Genomics Research and Innovation, NABDA/FMST, Abuja, Nigeria
Tamas Korcsmaros
Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
José Manuel Martín-Villa
Department of Immunology, Complutense University and IIS Gregorio Marañón, Madrid, Spain
Pablo Barreiro
UNIR Health Sciences School & Medical Center, Madrid, Spain; Emergency Hospital Isabel Zendal, Madrid, Spain
Octavio Corral
UNIR Health Sciences School & Medical Center, Madrid, Spain
Vicente Soriano
UNIR Health Sciences School & Medical Center, Madrid, Spain
Summary: Characterization of host genetic factors contributing to COVID-19 severity promises advances on drug discovery to fight the disease. Most genetic analyses to date have identified genome-wide significant associations involving loss-of-function variants for immune response pathways. Despite accumulating evidence supporting a role for T cells in COVID-19 severity, no definitive genetic markers have been found to support an involvement of T cell responses. We analyzed 205 whole exomes from both a well-characterized cohort of hospitalized severe COVID-19 patients and controls. Significantly enriched high impact alleles were found for 25 variants within the T cell receptor beta (TRB) locus on chromosome 7. Although most of these alleles were found in heterozygosis, at least three or more in TRBV6-5, TRBV7-3, TRBV7-6, TRBV7-7, and TRBV10-1 suggested a possible TRB loss of function via compound heterozygosis. This loss-of-function in TRB genes supports suboptimal or dysfunctional T cell responses as a major contributor to severe COVID-19 pathogenesis.
