Rationale An estimated 25 million people worldwide have one deleterious variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic respiratory disease symptoms are at an increased prevalence in cystic fibrosis (CF) heterozygotes. Objectives Determine the level of CFTR function in CF heterozygotes compared to individuals without CF-causing variants. Establish whether CFTR function differs between asymptomatic and symptomatic CF heterozygotes. Methods Individuals without respiratory symptoms or CF family history were recruited as controls. Heterozygotes were recruited from families with a CF individual harboring null alleles or c.1521_1523del (F508del) in CFTR. CFTR function was measured by short circuit current in primary human nasal epithelial cells (HNEs) from participants. Cell composition was assessed by single cell RNA sequencing. Measurements and Main Results CFTR function was variable in cells from control and heterozygous individuals. Mean CFTR function in asymptomatic null (8.8{+/-}0.5A/cm2 (SEM); n=30) and F508del (8.7{+/-}1.0A/cm2 ; n=22) heterozygotes was similar and significantly lower at 54.6% and 53.9% than controls (16.1{+/-}1.1A/cm2 ; n=24; p<0.0001). Mean CFTR function in symptomatic heterozygotes (8.4{+/-}1.0A/cm2 ; n =15) was 52.1% of controls and did not differ from asymptomatic heterozygotes (p=0.7803). Cell identities and proportions were equivalent between control and heterozygous cultures. HNEs from CF heterozygotes showed variable response to CFTR modulators. Conclusions CFTR function in primary airway cells exhibits substantial interindividual variability and overlaps between controls and CF heterozygotes. CF heterozygotes exhibit approximately 50% of CFTR function in controls, regardless of symptom status. These findings suggest that respiratory symptoms in CF heterozygotes are influenced by factors beyond CFTR dysfunction.
Pion, A., Chang, A., Mejia, P., Eastman, A. C., Kavanagh, E., Topasna, A., Starego, K., Parr, A., Raraigh, K. S., Merlo, C., Sharma, N., Cutting, G.
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