The profile of blood methylation is associated with disease severity in bronchiectasis

<bold>Introduction:</bold> DNA methylation integrates host exposures and can lead to cellular changes and influence disease status. This has not been explored before in bronchiectasis (BE). Here we studied the association of the blood DNA methylation profile with BE severity (measured by the Bronchiectasis Severity Index) (BSI), and type and intensity of lung inflammation. <bold>Methods:</bold> The blood DNA methylation profile was determined in 167 clinically stable BE patients (Illumina 850k), split into a discovery (n=94) and a validation cohort (n=73). Differentially methylated positions (DMPs) associated with BSI were determined using sex-adjusted linear models. Gene set Enrichment Analysis was used for functional enrichment. Blood RNA-seq was studied in a subset of patients (n=57), and sputum neutrophil elastase levels were measured by ELISA in these patients. <bold>Results:</bold> In the discovery cohort we identified 251 BSI-associated DMPs (p-aj<0.05), 89% of which were hypomethylated in more severe patients (BSI>9); 98% of them were validated in the second cohort. BSI-associated DMPs were enriched in leukocyte activation, migration and adhesion pathways. Methylation and mRNA expression levels were significantly related to 35 DMPs, which were associated with neutrophils, T and B cells. Finally, the methylation and expression levels of 12 DMPs were related to sputum neutrophil elastase levels. <bold>Conclusion:</bold> Severe BE patients have a distinct blood methylation profile, associated with functional changes and lung inflammation, suggesting a systemic effect of BE, and identifying potential novel biomarkers and therapeutic targets. <bold>Funding:</bold> Instituto de Salud Carlos III (PI21/00419), SEPAR 2023, Serra Hunter Program.