Abstract:
Background: Heterozygote carriers of potentially pathogenic
variants in the cystic fibrosis transmembrane conductance regulator
(CFTR ) gene have increased asthma risk. However, the frequency
and impact of CFTR variation among individuals with asthma is
unknown.
Objective: To determine whether potentially
pathogenic CFTR variants associate with disease severity and
whether individuals with two potentially pathogenic variants exist in a
severe asthma-enriched cohort .
Methods : We analyzed sequencing data spanning a 190.5Kb region
of CFTR in participants from the Severe Asthma Research Program
(SARP1-3). Potentially pathogenic, rare CFTR variants
(frequency<0.05) were classified as CF-causing or of varying
clinical consequences (VVCC) (CFTR2.org). Regression-based models tested
for association between CFTR genotypes (0-2 potentially
pathogenic variants) and severity outcomes.
Results: Of 1401 participants, 9.5% (134) had one potentially
pathogenic variant, occurring more frequently in non-Hispanic white
(NHW, 10.1% [84 of 831]) compared to African American individuals
(AA, 5.2% [22 of 426]). We found ≥2 potentially
pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and
2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes
(≥1 or ≥2 variants) were not cumulatively associated with lung function
or exacerbations. In NHW, we found three F508del compound heterozygotes
with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and
one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12.Conclusions: We found potentially
pathogenic CFTR variants within a severe asthma-enriched cohort ,
including three compound heterozygote genotypes variably associated with
CF in NHW individuals. These findings provide the rationale
for CFTR sequencing and phenotyping of CF-related traits in
individuals with severe asthma.