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Background  Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the  CFTR  gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients.    Results  We profiled DNA methylation at  CFTR , the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ≥18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific  trans -factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity:  HMOX1  and  GSTM3  in nasal epithelial samples;  HMOX1  and  EDNRA  in blood samples. The association between pulmonary severity and DNA methylation at  EDNRA  was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at  GSTM3  were associated with the  GSTM3*B  allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis.    Conclusions  DNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of  CFTR  and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity.    Electronic supplementary material  The online version of this article (doi:10.1186/s13148-016-0300-8) contains supplementary material, which is available to authorized users.

DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis