Cystic fibrosis is classically presented as a monogenic disease, caused by variants in the CFTR gene (Cystic Fibrosis Transmembrane conductance Regulator), which encodes a chloride channel expressed in epithelia. Impaired synthesis or function of the CFTR protein reduces chloride ion permeability and the hydration of secretions, which become viscous and primarily affect the lungs, the digestive tract, the pancreas, the liver and the biliary tract. More than 2,000 variants have been described and grouped into six classes according to their functional consequences, a distinction that carries therapeutic significance since CFTR modulators target specific classes. Yet, apart from exocrine pancreatic status, most studies—including those in twins and siblings—conclude that there is a weak association between CFTR variants and the clinical phenotypes observed.
This review seeks to explain the extreme clinical heterogeneity of the disease, which affects approximately 80,000 patients worldwide. Environmental factors account for nearly 50% of the variability in pulmonary function, but patients carrying similar variants and sharing the same environment can present with very different manifestations. This residual variability is attributed to genetic variants located outside the CFTR locus, referred to as "modifier genes." The authors review the work that has associated such factors with the various phenotypes, whether respiratory involvement, meconium ileus, cystic fibrosis–related diabetes or liver disease. The SLC26A9 and SLC6A14 genes recur frequently, whereas SERPINA1 is the only gene whose association with the severity of liver involvement has been successfully replicated.
A substantial section is devoted to the variability of the response to CFTR modulators, which is also partly explained by modifier genes. For ivacaftor, the mean improvement in respiratory function reaches 10.4% at 24 weeks, but with a dispersion of ±15.5% across patients; this variability has been linked to the SLC26A9 gene. The team reports its own analyses of the response to the lumacaftor–ivacaftor combination: from a cohort of 4,981 patients, 765 were included, demonstrating a respiratory and nutritional gain sustained over two years, more pronounced in the most severely affected patients, and an association between the rs12839137 variant of SLC6A14 and the nutritional response.
The authors highlight the limitations of candidate-gene approaches, which are often not replicated and whose functionality remains poorly explored. They advocate for hypothesis-free studies and for functional validation of modifier genes, steps necessary for the establishment of polygenic risk scores. Such genomic knowledge would pave the way for a personalized, predictive and preventive medicine of cystic fibrosis.