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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • COVID-19* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis* / pathology
  • Heterozygote
  • Humans

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • CFTR protein, human

Grants and funding

This research was funded by the private donors for the support provided to AR (Department of Medical Biotechnologies, University of Siena) for the COVID-19 host genetics research project (D.L n.18 of 17 March 2020). We also thank the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/, accessed on 3 November 2022), MIUR project ‘Dipartimenti di Eccellenza 2018–2020’ to the Department of Medical Biotechnologies University of Siena, Italy, and ‘Bando Ricerca COVID-19 Toscana’ project to Azienda Ospedaliero-Universitaria Senese. We thank Intesa San Paolo for the 2020 charity fund dedicated to the project N B/2020/0119 “Identificazione delle basi genetiche determinanti la variabilità clinica della risposta a COVID-19 nella popolazione italiana”. The Italian Ministry of University and Research for funding within the “Bando FISR 2020” in COVID-19 fo the project “Editing dell’RNA contro il SARS-CoV-2: hackerare il virus per identificare bersagli molecolari e attenuare l’infezione—HACKTHECOV) and the Istituto Buddista Italiano Soka Gakkai for funding the project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19” (ID n. 2020-2016_RIC_3). We thank EU project H2020-SC1-FA-DTS-2018-2020, entitled “International consortium for integrative genomics prediction (INTERVENE)”—Grant Agreement No. 101016775. Generous support was also received from private donations by Maurizio Traglio, Enzo Cattaneo, and Alberto Borella. Work in NP lab was supported by grants from the Italian Cystic Fibrosis Foundation (FFC #10/2021; with the contribution of “Delegazione di Genova”, “Delegazione Altomilanese”, “Gruppo di sostegno di Campiglione Fenile”, and “Delegazione di Napoli”), the Cystic Fibrosis Foundation (PEDEMO20G0) and the Italian Ministry of Health (Ricerca Corrente and 5permille).