EAACI ISAF-RHINA Congress 2025
Epigenome-wide association study of the nasal microbiome involved in asthma exacerbations in severe asthma patients
Erick Castillo-Vargas, MSc1, Mario Martin-Almeida, MSc1, Elena Martin-Gonzalez, MSc1, Ruperto González-Pérez, MD, PhD2, José M. Hernández-Pérez, MD, PhD3,4, Olaia Sardón-Prado, MD, PhD5,6, Paloma Poza-Guedes, MD, PhD2, Elena Mederos-Luis, MD7, Paula Corcuera-Elosegui, MD, PhD5, Inmaculada Sánchez-Machín, MD, PhD7, Leyre López-Fernández, MD5, Jesús Villar, MD, PhD8,9,10,11, Andres Cardenas, PhD12, Fabian Lorenzo-Diaz, PhD1, Maria Pino-Yanes, PhD1,8,13, Javier Perez-Garcia, PhD1,12
1 Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain.
2 Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
3 Pulmonary Medicine Service, Hospital Universitario de N.S de Candelaria, La Laguna, Tenerife, Spain.
4 Pulmonary Medicine Section, Hospital Universitario de La Palma, La Palma, Spain.
5 Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain.
6 Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
7 Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
8 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
9 Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
10 Faculty of Health Sciences, Universidad del Atlántico Medio, Tafira Baja, Las Palmas, Spain.
11 Li Ka Shing Knowledge Institute at the St. Michael’s Hospital, Toronto, Ontario, Canada.
12 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, USA.
13 Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain.
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: We analyzed nasal and blood samples from 171 adults and 51 children from the Genomics and Metagenomics of Asthma Severity (GEMAS) study. The nasal microbiome was profiled by 16S-rRNA gene sequencing (V3-V4 regions) and the blood methylome with the Illumina EPICv1 array. We conducted epigenome‐wide association studies by testing 709,923 CpGs with 3 diversity indices (Observed, Shannon, and Faith) and 12 bacterial genera associated with asthma exacerbations and meta-analyzed age groups. Regression models were adjusted for age, sex, ancestry, and cell heterogeneity. We identified differentially methylated regions (DMRs) and subjected them to enrichment analysis. Multiple comparisons were adjusted using a false discovery rate (FDR)<0.05.
Results: We analyzed 222 participants, with a mean age of 10.5 (±1.9) years for children and 46.5 (±18.4) years for adults; 63% were female and 87% had severe asthma. DNAm levels at 31 CpGs were significantly associated with Dolosigranulum, Fusobacterium, Leptotrichia, Porphyromonas, and Streptococcus, and the Faith and Observed diversity indices (FDR<0.05). These included genes previously related to asthma (OSBPL5, SIGLECP3, and EXOC4). We also identified 234 and 103 DMRs associated with the 12 exacerbation‐related bacterial genera and the 3 alpha diversity indices, respectively. Top hit DMRs were located in genes implicated in asthma pathogenesis and control and other pulmonary diseases (HOXB6: 3 CpGs, p=4.2x10-9; ZBTB38: 5 CpGs, p=9.1x10-17; TAGLN: 4 CpGs, p=6.4x10-11; GNA12: 3 CpGs, p=4.7x10-10; ZNF415: 5 CpGs, p=3.5x10-13). DMRs were enriched in genes involved in the Wnt signaling pathway (adjusted p=0.008) and the catenin complex (adjusted p=0.03). The Wnt signaling pathway drives events involved with inflammation, airway remodeling, and airway hyper-responsiveness, being suggested as a novel therapeutic target for asthma. Additionally, evidence has implicated both β-catenin-dependent and β-catenin-independent Wnt axes in asthma.
Conclusion: We revealed novel associations between blood DNAm and nasal bacteria involved in asthma exacerbations in severe asthma patients, suggesting the role of the asthma-related Wnt signaling pathway in host-microbiome interactions.
Funding: Fundación DISA (009/2024), MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00).