Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

  • Cells. 2022 Dec 16;11(24):4096. doi: 10.3390/cells11244096.
Margherita Baldassarri  1  2 ,  Kristina Zguro  2 ,  Valeria Tomati  3 ,  Cristina Pastorino  3  4 ,  Francesca Fava  1  2  5 ,  Susanna Croci  1  2 ,  Mirella Bruttini  1  2  5 ,  Nicola Picchiotti  6  7 ,  Simone Furini  2 ,  Nicoletta Pedemonte  3 ,  Chiara Gabbi  8 ,  Alessandra Renieri  1  2  5 ,  Chiara Fallerini  1  2 ,  Gen-Covid Multicenter Study
Affiliations
  • 1. Medical Genetics, University of Siena, 53100 Siena, Italy.
  • 2. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
  • 3. UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16148 Genova, Italy.
  • 4. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16126 Genoa, Italy.
  • 5. Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy.
  • 6. Department of Mathematics, University of Pavia, 27100 Pavia, Italy.
  • 7. University of Siena, DIISM-SAILAB, 53100 Siena, Italy.
  • 8. Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden.
PMID: 36552859 DOI: 10.3390/cells11244096
Abstract

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
CFTR complex alleles; COVID-19; post-Mendelian model.
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