Introduction
Cystic fibrosis (CF) is a disease of the airways that occurs most
commonly in individuals of European descent, but can occur in
individuals of any race or ethnicity. CF is caused by variants in the
cystic fibrosis transmembrane conductance regulator (CFTR ) gene
and characterized by bronchiectasis with a subgroup of individuals
experiencing overlapping features with a much more common airways
disease, asthma. A historical study showed that up to 50% of
individuals with CF had airway reactivity thought to be related to the
severity of lung disease. More recently, the 2020 US CF Foundation
Patient Registry has reported the prevalence for CF-asthma overlap to be
31.1% which contrasts to general population estimates of
7.8%(1). Epidemiologic data published in general
populations and resulting meta-analyses have also demonstrated an
increased risk of asthma in heterozygous carriers of pathogenicCFTR variants.(2) Most of this risk has been
attributed to heterozygote carriers of the common pathogenic CFTR
variant, c.1521_1523delCTT (p.Phe508del; legacy: F508del), in whom lung
function impairment has also been reported among those with asthma from
a general population.(3) The biologic plausibility ofCFTR as an asthma risk modifier locus is supported by animal
models reporting increased airway responsiveness independent of mucous
plugging and inflammation. The limitations of these prior studies are
that they (1) primarily used targeted genotyping rather than sequencing
which can miss numerous potentially pathogenic variants, (2) the
diagnosis of asthma was based on a physician’s diagnosis which can be
prone to misclassification, and (3) that these studies focused on asthma
risk and not severity. We report a sequencing-based study of the CFTR
locus to identify and evaluate the clinical impact of potentially
pathogenic CFTR variation in a multi-racial/ethnic asthma cohort
enriched for severe disease, the NHLBI-sponsored Severe Asthma Research
Program (SARP1-3). Furthermore, because highly effective therapies
targeting the CFTR protein (CFTR modulators) are approved and available,
identification of pathogenic CFTR variants in this population may have
important therapeutic implications.(4)