Clinical and primary cell evidence reveals complex CFTR function-phenotype relationships

The CFTR function-phenotype relationship remains incompletely understood, with prior work yielding heterogeneous findings suggesting linear and nonlinear associations.

Define the genotype-function-phenotype relationship using data from the Clinical and Functional TRanslation of CFTR (CFTR2) and human nasal epithelial (HNE) studies.

Clinical data (sweat chloride, lung function, pancreatic status) from 84,418 individuals in CFTR2 were linked to CFTR functional measures derived from 289 CFTR genotypes. Total genotype function was calculated as the average percent wild-type chloride conductance of both variants in heterologous cell lines. This framework was applied to an HNE cohort including people with CF, CF heterozygotes, and controls. CFTR function was derived from short circuit measurements in HNEs from 153 individuals and correlated with phenotype for 415 individuals. Weighted linear and logarithmic regressions were applied to evaluate the function-phenotype relationship.

Simple linear regression obscured marked heterogeneity across datasets. Piecewise linear regressions revealed marked attenuation of slope magnitude with increasing function across phenotypes. This pattern was well-described by a logarithmic function, such that modeling function on a log scale rendered the relationship approximately linear. HNE data demonstrated similar attenuation, corroborating this pattern.

Large-scale natural history data integrated with primary cell findings show that the function-phenotype relationship is not sufficiently described by a single linear effect but is a proportional relationship, in which equivalent changes in CFTR function yield different phenotypic outcomes depending on baseline function. This framework provides precision in predicting clinical benefits from CFTR-directed therapies and identifying meaningful thresholds of CFTR rescue.

This work integrates registry and primary cell data to define the relationship amongst CFTR genotype, CFTR protein function, and clinical phenotype. These findings establish reference points for evaluating the degree of phenotypic improvement anticipated from functional restoration from CFTR-targeted treatments. More broadly, this study advances the understanding of CF disease mechanisms by linking molecular function to real-world clinical outcomes across data sources.

Scientific Knowledge on the Subject: The relationship between CFTR function and clinical phenotype remains incompletely understood. Prior studies have suggested both linear and nonlinear associations between CFTR activity and disease manifestations. Defining this relationship is increasingly important for interpreting functional data and predicting clinical benefit from CFTR-directed therapies.What This Study Adds to the Field: Using clinical and functional data from more than 84,000 individuals in CFTR2 together with primary human nasal epithelial cell measurements spanning people with cystic fibrosis, carriers, and unaffected controls, we demonstrate that the CFTR function-phenotype relationship is not adequately described by a single linear model. Instead, the relationship is best fitted by piecewise linear regressions of varying slope conforming to a logarithmic pattern, with the greatest phenotypic gains occurring at the lowest levels of baseline CFTR function. These findings provide a quantitative framework for interpreting functional rescue and predicting therapeutic benefit across the CFTR functional spectrum.