Unraveling the CFTR Function–Phenotype Connection for Precision Treatment in Cystic Fibrosis
Authors: Edith T. Zemanick, Deepika Polineni
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Unraveling the CFTR Function-Phenotype Connection for Precision Treatment in Cystic FibrosisThe clinical phenotype of cystic fibrosis (CF), chronic infection, and inflammation leading to progressive obstructive lung disease and pancreatic insufficiency is caused by absence or dysfunction of the CFTR (cystic fibrosis transmembrane conductance regulator) protein (1).More than 2,000 variants of CFTR have been described, and these mutations are largely categorized based on the mechanism of impairment (2).Loss-of-function mutations (class I-III) result in little to no functional CFTR protein and are associated with a classic CF phenotype.Although there is a high degree of individual variation, people with at least one residual function mutation (class IV-VI) have some functional CFTR and more often have a clinical phenotype characterized by preserved pancreatic function and mild lung disease.Sweat chloride measurements have been used as a surrogate marker of CFTR function (3), with values observed to be higher in individuals homozygous for class I-III mutations than in heterozygotes with at least one residual function mutation (4).As lower sweat chloride values are associated with improved survival (4), these observations have led to the hypothesis that increasing CFTR function, even to a partial degree, would result in improved clinical phenotypes.CFTR modulators have been shown to increase CFTR function in genotypespecific patient populations, including many with class III ("gating") mutations or residual function mutations, and for F508del homozygotes (5).With the advent of modulator therapies, the need to predict drug responsiveness and establish how CFTR functional improvements translate to phenotypic changes has gained new urgency.In this issue of the Journal, McCague and colleagues (pp.1116-1126) (6) attempt to address these questions using data collected for the Clinical and Functional Translation of CFTR (CFTR2) project ( 7).The vast CFTR2 database contains clinical and genetic information from 88,664 individuals with CF worldwide, as well as functional data associated with specific genetic variants.Leveraging in vitro studies that characterized genetic variant-specific responses to modulators, the investigators determined the percentage of CFTR activity relative to the wild-type in 54,671 individuals with 226 unique genotypes, and determined correlations with pancreatic function, lung disease, and sweat chloride.The investigators focused on individuals with CFTR function ranging from 0.85% to 50%, with 0.85% corresponding to those with one F508del mutation and a second mutation expected to result in no CFTR activity (NULL), and .50%indicating adequate CFTR to prevent disease.The investigators found a strong correlation between CFTR function and sweat chloride, and a less striking but still significant association with lung function and pancreatic status.Importantly, the relationship between CFTR function and clinical phenotype was observed to be logarithmic, suggesting that small increases in