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)