Blood DNA methylation profile is altered in severe bronchiectasis.

Rationale: Bronchiectasis is a chronic lung respiratory disease whose systemic aspect is poorly understood. We aimed to characterise the blood DNA methylation profiles of bronchiectasis patients and to determine the relationship of these profiles with disease severity and their functional relevance to circulating immune cells. Methods: Whole-genome DNA methylation was measured in blood from 165 bronchiectasis patients (Illumina 850k). The cohort was divided into discovery (n=94) and validation (n=71) sets. Differentially methylated positions (DMPs) associated with the Bronchiectasis Severity Index (BSI) were determined using sex-adjusted linear models. To explore functional relevance, whole-blood RNA sequencing was performed in a subset of patients. Blood immune cell proportions deconvoluted from methylation data were identified, clustered with gene expression and linked to BSI variables. An elastic net model was constructed to validate the results. Results: We identified 100 BSI-associated DMPs, 98% of which were hypomethylated in severe patients (BSI score ≥9). BSI-associated DMPs were enriched in leukocyte activation, secretion, immunoglobulin production and tissue remodelling. Of these DMPs, 15 (annotated to 16 genes) exhibited significant correlations between methylation and gene expression levels. Three of them ( Conclusion: Severe bronchiectasis patients presented an altered blood epigenetic profile, which was influenced by blood neutrophils. These findings suggest that bronchiectasis has systemic implications, especially for the most severely affected patients.