Cells (Dec 2022)

Gain- and Loss-of-Function <i>CFTR</i> Alleles Are Associated with COVID-19 Clinical Outcomes

  • Margherita Baldassarri,
  • Kristina Zguro,
  • Valeria Tomati,
  • Cristina Pastorino,
  • Francesca Fava,
  • Susanna Croci,
  • Mirella Bruttini,
  • Nicola Picchiotti,
  • Simone Furini,
  • GEN-COVID Multicenter Study,
  • Nicoletta Pedemonte,
  • Chiara Gabbi,
  • Alessandra Renieri,
  • Chiara Fallerini

DOI
https://doi.org/10.3390/cells11244096
Journal volume & issue
Vol. 11, no. 24
p. 4096

Abstract

Read online

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19.

Keywords