Epigenome-Wide Association Study of the Upper-Airway Microbiome Involved in Asthma Exacerbations
Abstract
RationaleThe role of DNA methylation (DNAm) markers in the upper-airway microbiome related to asthma exacerbations despite inhaled corticosteroid (ICS) treatment is unexplored.
ObjectivesTo identify whole-blood DNAm markers associated with the upper-airway microbiome related to asthma exacerbations despite ICS treatment.
MethodsWe analyzed salivary, nasal, and pharyngeal microbiome in 242 asthma patients (GEMAS) for discovery. We tested associations between whole-blood DNAm at 703,505 CpGs and 21 exacerbation-related microbiome traits. Replication for the nasal microbiome was evaluated in 272 (Project Viva) and 66 (SysPharmPediA) children with and without asthma. We analyzed differentially methylated regions (DMRs), gene enrichment, associations with blood gene expression (RNA-seq, n=119), and DNAm predictors of plasma proteins.
Measurements and Main ResultsWhole-blood DNAm at 73 CpGs and 550 DMRs was associated with 17 exacerbation-related microbiome traits (false discovery rate [FDR]<0.05), including genes implicated in immune and inflammatory responses and the 17q12-q21 asthma locus ORMDL3. Most CpGs were associated with Campylobacter (pharyngeal) and Leptotrichia (nasal) abundance. Ten DNAm markers were replicated (p<0.05), including the corticosteroid insensitivity-related gene PTPRR associated with nasal bacterial richness. Enrichment analyses identified genes related to diabetes, obesity, smoking, TGF-{beta}, MAPK, and Wnt signaling and regulated by trichostatin A, NF-{kappa}B, and the glucocorticoid receptor (FDR<0.05). The CpG cg18994033, associated with pharyngeal Tannerella, was associated with ITM2C whole-blood expression. Nine DNAm-predicted plasma proteins involved in inflammation, tissue remodeling, and TGF-{beta} signaling were associated with seven exacerbation-related microbiome traits, including Streptococcus and Selenomonas.
ConclusionsWhole-blood DNAm markers implicated in inflammation, immunity, and asthma comorbidities were associated with the upper-airway microbiome linked to asthma exacerbations.
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BibTeX
@misc{castillovargas2026epigenomewide,
title = {{Epigenome-Wide Association Study of the Upper-Airway Microbiome Involved in Asthma Exacerbations}},
author = {E. Castillo-Vargas and M. Martin-Almeida and A. K. Bozack and E. L. Garcia and E. Martin-Gonzalez and R. Gonzalez-Perez and J. M. Hernandez-Perez and O. Sardon-Prado and P. Poza-Guedes and E. Mederos-Luis and P. Corcuera-Elosegui and I. Sanchez-Machin and L. Lopez-Fernandez and S. L. Rifas-Shiman and S. Hashimoto and S. J. H. Vijverberg and A. H. Neerincx and H. Buntrock-Döpke and M. Gorenjak and A. A. Toncheva and S. Harner and S. Brandstetter and C. Wolff and U. Potocnik and M. Kabesch and A. D. Kraneveld and J. Villar and M.-F. Hivert and E. Oken and D. R. Gold and M. I. Abdel-Aziz and A. H. Maitland-van der Zee and A. Cardenas and F. Lorenzo-Diaz and Pino},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.26364005},
url = {https://www.medrxiv.org/content/10.64898/2026.10.02.26364005v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Epigenome-Wide Association Study of the Upper-Airway Microbiome Involved in Asthma Exacerbations
AU - E. Castillo-Vargas
AU - M. Martin-Almeida
AU - A. K. Bozack
AU - E. L. Garcia
AU - E. Martin-Gonzalez
AU - R. Gonzalez-Perez
AU - J. M. Hernandez-Perez
AU - O. Sardon-Prado
AU - P. Poza-Guedes
AU - E. Mederos-Luis
AU - P. Corcuera-Elosegui
AU - I. Sanchez-Machin
AU - L. Lopez-Fernandez
AU - S. L. Rifas-Shiman
AU - S. Hashimoto
AU - S. J. H. Vijverberg
AU - A. H. Neerincx
AU - H. Buntrock-Döpke
AU - M. Gorenjak
AU - A. A. Toncheva
AU - S. Harner
AU - S. Brandstetter
AU - C. Wolff
AU - U. Potocnik
AU - M. Kabesch
AU - A. D. Kraneveld
AU - J. Villar
AU - M.-F. Hivert
AU - E. Oken
AU - D. R. Gold
AU - M. I. Abdel-Aziz
AU - A. H. Maitland-van der Zee
AU - A. Cardenas
AU - F. Lorenzo-Diaz
AU - Pino
PY - 2026
DA - 2026/10/02
PB - medRxiv
DO - 10.64898/2026.10.02.26364005
UR - https://www.medrxiv.org/content/10.64898/2026.10.02.26364005v1
AB - RationaleThe role of DNA methylation (DNAm) markers in the upper-airway microbiome related to asthma exacerbations despite inhaled corticosteroid (ICS) treatment is unexplored. ObjectivesTo identify whole-blood DNAm markers associated with the upper-airway microbiome related to asthma exacerbations despite ICS treatment. MethodsWe analyzed salivary, nasal, and pharyngeal microbiome in 242 asthma patients (GEMAS) for discovery. We tested associations between whole-blood DNAm at 703,505 CpGs and 21 exacerbation-related microbiome traits. Replication for the nasal microbiome was evaluated in 272 (Project Viva) and 66 (SysPharmPediA) children with and without asthma. We analyzed differentially methylated regions (DMRs), gene enrichment, associations with blood gene expression (RNA-seq, n=119), and DNAm predictors of plasma proteins. Measurements and Main ResultsWhole-blood DNAm at 73 CpGs and 550 DMRs was associated with 17 exacerbation-related microbiome traits (false discovery rate [FDR]<0.05), including genes implicated in immune and inflammatory responses and the 17q12-q21 asthma locus ORMDL3. Most CpGs were associated with Campylobacter (pharyngeal) and Leptotrichia (nasal) abundance. Ten DNAm markers were replicated (p<0.05), including the corticosteroid insensitivity-related gene PTPRR associated with nasal bacterial richness. Enrichment analyses identified genes related to diabetes, obesity, smoking, TGF-{beta}, MAPK, and Wnt signaling and regulated by trichostatin A, NF-{kappa}B, and the glucocorticoid receptor (FDR<0.05). The CpG cg18994033, associated with pharyngeal Tannerella, was associated with ITM2C whole-blood expression. Nine DNAm-predicted plasma proteins involved in inflammation, tissue remodeling, and TGF-{beta} signaling were associated with seven exacerbation-related microbiome traits, including Streptococcus and Selenomonas. ConclusionsWhole-blood DNAm markers implicated in inflammation, immunity, and asthma comorbidities were associated with the upper-airway microbiome linked to asthma exacerbations.
ER -