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

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.

The Effect of Complex Alleles of the CFTR Gene on the Clinical Manifestations of Cystic Fibrosis and the Effectiveness of Targeted Therapy

“…The work also characterized complex CFTR alleles, including p.[Ala238Val;Phe508del], p.[Ala238Val;Phe508del], p.[Arg74Trp;Val201Met;Asp1270Asn], p.[Ile1027Thr;Phe508del], and p.[Ile1506Val;Asp1168Gly] ([I506V;D1168G]), and the simple variants p.Arg347Cys (R347C), p.Phe1052Val (F1052V), p.Tyr625Asn (Y625N), p.Ile328Val (I328V), p.Lys68Glu (K68E), p.Ala309Asp (A309D), p.Ala252Thr (A252T), p.Gly542Ter (G542X), p.Val562Ile (V562I), p.Arg1066His (R1066H), p.Ile506Val (I506V), and p.Ile807Met (I807M), which lead to a decrease in CFTR function and, thus, to a more severe COVID-19 course. Thus, the accurate genetic analysis of CFTR is an important tool for identifying patients at risk of severe COVID-19 [ 49 ].…”

Advances in the Study of Common and Rare CFTR Complex Alleles Using Intestinal Organoids

“…The I1027T variant is a polymorphism that does not cause CF. In a study by Baldassarri et al, the functional activity of the CFTR channel was assessed in individuals with [F508del;I1027T] [8]. The CFBE41o (human CF bronchial epithelial) cell line from a CF (F508del/F508del) patient was transfected with a plasmid carrying the CA [F508del;I1027T] [8].…”

“…In a study by Baldassarri et al, the functional activity of the CFTR channel was assessed in individuals with [F508del;I1027T] [8]. The CFBE41o (human CF bronchial epithelial) cell line from a CF (F508del/F508del) patient was transfected with a plasmid carrying the CA [F508del;I1027T] [8]. The assessment of the CFTR protein's functional activity showed that in the case of [F508del;I1027T], the CFTR channel function amounted to 23%, while in the control F508del it was 13%.…”

COVID-19 annual update: a narrative review

“…The candidate gene approach has also been widely used to confirm and complement GWAS-derived findings and provide useful information to identify specific pathways and proteins important in disease pathogenesis [ 1 , 68 , 69 ] (Fig. 3 ).…”

“…3 ). In this regard, it is interesting that impairment of CFTR function, resulting from certain alleles of this gene, is associated with the severity of COVID-19, which also appears to activate a synergistic effect with estrogens in the response to infection [ 69 ]. Numerous other candidate genes have been analyzed and validated by functional studies to provide relevant clinical information [ 70 , 71 ].…”