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C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age.
Zanella, Isabella; Zacchi, Eliana; Piva, Simone; Filosto, Massimiliano; Beligni, Giada; Alaverdian, Diana; Amitrano, Sara; Fava, Francesca; Baldassarri, Margherita; Frullanti, Elisa; Meloni, Ilaria; Renieri, Alessandra; Castelli, Francesco; Quiros-Roldan, Eugenia.
  • Zanella I; Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
  • Zacchi E; Clinical Chemistry Laboratory, Cytogenetics and Molecular Genetics Section, Diagnostic Department, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.
  • Piva S; Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.
  • Filosto M; Division of Infectious and Tropical Diseases, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.
  • Beligni G; University Division of Anesthesiology and Critical Care Medicine, ASST Spedali Civili, 25123 Brescia, Italy.
  • Alaverdian D; Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy.
  • Amitrano S; Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.
  • Fava F; NeMo-Brescia Clinical Center for Neuromuscular Diseases, 25064 Gussago, Italy.
  • Baldassarri M; Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
  • Frullanti E; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, 53100 Siena, Italy.
  • Meloni I; Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
  • Renieri A; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, 53100 Siena, Italy.
  • Castelli F; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, 53100 Siena, Italy.
  • Quiros-Roldan E; Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
Int J Mol Sci ; 22(13)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1288901
ABSTRACT
A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04-5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Microsatellite Repeats / C9orf72 Protein / COVID-19 Type of study: Cohort study / Observational study / Prognostic study / Randomized controlled trials Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22136991

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Microsatellite Repeats / C9orf72 Protein / COVID-19 Type of study: Cohort study / Observational study / Prognostic study / Randomized controlled trials Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22136991