Neumocan Congress 2025
Abstract
Background: Genetic variation influences the nasal microbiome associated with asthma exacerbations, yet the contribution of DNA methylation (DNAm) remains unknown. This study aimed to identify leukocyte epigenetic markers linked to nasal bacterial taxa related to asthma exacerbations.
Methods: Nasal and blood samples from 171 adults and 51 children of the GEMAS cohort were analyzed. DNA methylation was assessed using the Illumina EPICv1 array, and the nasal microbiome was profiled by 16S rRNA gene sequencing (V3–V4 regions). Epigenome- and microbiome-wide association studies were conducted to evaluate 709,923 CpG sites in relation to three alpha diversity indices (Observed, Shannon, and Faith) and twelve bacterial genera previously associated with asthma exacerbations. Results were meta-analyzed across age groups. Regression models were adjusted for age, sex, ancestry, and cell-type heterogeneity. Differentially methylated regions (DMRs) were identified and subjected to enrichment analyses. Multiple testing correction was performed using a false discovery rate (FDR) threshold of <0.05.
Results: Methylation at 31 CpG sites was significantly associated (FDR < 0.05) with the bacterial genera Dolosigranulum, Fusobacterium, Leptotrichia, Porphyromonas, and Streptococcus, as well as with the Faith and Observed diversity indices. Several associated CpGs mapped to genes previously implicated in asthma (OSBPL5, SIGLECP3, EXOC4). A total of 234 DMRs were associated with the 12 asthma-related genera and 103 DMRs with the three alpha diversity indices. The most significant DMRs were located in genes relevant to asthma and other pulmonary diseases (HOXB6: 3 CpGs, p = 4.2×10−9; ZBTB38: 5 CpGs, p = 9.1×10−17; TAGLN: 4 CpGs, p = 6.4×10−11; GNA12: 3 CpGs, p = 4.7×10−10; ZNF415: 5 CpGs, p = 3.5×10−13). Enrichment analysis revealed an overrepresentation of DMRs within the Wnt signaling pathway (adjusted p = 0.008). The Wnt pathway regulates inflammation, airway remodeling, and bronchial hyperreactivity, and has been proposed as a novel therapeutic target in asthma.
Conclusion: These novel associations between blood DNA methylation and nasal bacteria involved in asthma exacerbations suggest that host–microbiome interactions may influence the Wnt signaling pathway through epigenetic mechanisms.
Funding: Fundación DISA (009/2024), MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00).