Abstract
Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory andgastrointestinal systems. No curative treatments are available, but the follow-up in specializedcenters has greatly improved the patient life expectancy. Robust biomarkers are required to monitorthe disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In thepresent study, we outline a strategy to select putative DNA methylation biomarkers of lung diseaseseverity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkersusing a genome-wide DNA methylation dataset that we generated in nasal epithelial samples fromthe MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cellsamples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site(ATP11Agene) positively correlated with lung function and BMI, and negatively correlated with lungdisease severity,P. aeruginosachronic infection, and the number of exacerbations. These results werereplicated in prospective sputum samples collected at four time points within an 18-month periodand longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates withCF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out thefirst longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker couldbe used to stratify CF patients in clinical trials.