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| Home > Articles > Published articles > Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19 |
(Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Cáncer) (Centro de Investigación Biomédica en Red de Cáncer) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitat de Barcelona) (Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Cáncer) (Universitat Internacional de Catalunya) (Centro de Investigación Biomédica en Red de Cáncer)
| Date: | 2021 |
| Abstract: | Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14. 3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c. 644A>G; p. (Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c. 2797T>C; p. (Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions. |
| Grants: | European Commission. Horizon 2020 779257 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR1282 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR496 Instituto de Salud Carlos III PI19/00553 Fundació la Marató de TV3 202115-30-31 |
| Note: | Contract grant sponsor: the Carlos III National Health Institute funded by FEDER funds - a way to build Europe - [PI19/00553 and CIBERONC]; the Government of Catalonia [2017SGR1282 and 2017SGR496]. AH is supported by the Solve-RD project. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. FV was supported by a ZonMW (The Netherlands Organization for Health Research and Development) Vidi grant (No. 91718351). This research was part of the Netherlands X-omics Initiative and partially funded by NWO (The Netherlands Organization for Scientific Research; project 184.034.019). |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | Frontiers in immunology, Vol. 12 (23 2021) , p. 719115, ISSN 1664-3224 |
