DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study.

Fanny Pineau,Sylvie Taviaux,Laura Brosseau,Davide Caimmi,Mireille Claustres,Isabelle Vachier,Raphaël Chiron,Margot Drevait,Albertina De Sario,Isabelle Rivals,Maurane Reveil

doi:10.3390/genes12030441

Abstract

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

Highlights

Mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene result in Cystic Fibrosis (CF, OMIM 219700), the most common life-shortening genetic disease in Caucasians
We showed that DNA methylation levels correlated with FEV1 %, in nasal epithelial cell samples from Cystic fibrosis (CF) patients [13]
42% of CF patients were treated with the modulator lumacaftor/ivacaftor [23]

Summary

Introduction

Mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene result in Cystic Fibrosis (CF, OMIM 219700), the most common life-shortening genetic disease in Caucasians (for a review see in [1]). The CFTR gene encodes a cAMP-dependent anion channel that is vital for bicarbonate (HCO3-) and chloride (Cl-) transport across the apical membrane of various epithelial cells. CFTR dysfunction or loss causes a severe imbalance in ion and water transport in multiple organs of the respiratory, digestive, and reproductive systems. The mutant CFTR protein is responsible for an altered innate and adaptive immune function and for a defective dampening of the inflammatory response. Pulmonary disease, which is characterized by chronic airway inflammation, recurrent infections, and progressive lung function decline, is the most common cause of morbidity and mortality in CF [2]. A number of comorbidities become more prevalent among CF patients, namely, diabetes and liver disease [2]

Methods

Results

Conclusion