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International audience; Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.

International audience; Twin and sibling studies have shown that lung disease severity is variable among cystic fibrosis (CF) patients and affected to the same extent by genetic and nonheritable factors. Genetic factors have been thoroughly assessed, whereas the molecular mechanisms whereby nonheritable factors contribute to the phenotypic variability of CF patients are still unknown. Epigenetic modifications may represent the missing link between nonheritable factors and phenotypic variation in CF. Herein, we review recent studies showing that DNA methylation is altered in CF and we address three possible factors responsible for these variations: (i) overproduction of reactive oxygen species, (ii) depletion of DNA methylation cofactors and (iii) susceptibility to acute and chronic bacterial infections. Also, we hypothesize that the unique DNA methylation profile of each patient can modulate the phenotype and discuss the interest of implementing integrated genomic, epigenomic and transcriptomic studies to further understand the clinical diversity of CF patients (Graphical Abstract).