II Early Career Investigators' Congress on Bio-Organic Research
Epigenome-wide association study in blood of the salivary microbiome involved in asthma exacerbations
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 salivary microbiome associated with asthma exacerbations, yet the contribution of DNA methylation (DNAm) is unknown. The study aimed to identify leukocyte epigenetic markers linked to salivary bacterial taxa implicated in asthma exacerbations.
Methods: We analyzed saliva and blood samples from 197 patients from the GEMAS study. The salivary 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 analyses on 693,029 CpGs with diversity indices and 3 bacterial genera associated with asthma exacerbations in this cohort. Models were adjusted for age, sex, ancestry, and tissue heterogeneity. We identified differentially methylated regions (DMRs) using dmrff and evaluated them in a pathway enrichment analysis using Enrichr. Multiple comparisons were adjusted using a false discovery rate (FDR)<0.05.
Results: DNAm levels at cg07977900 (RUBCN) were genome-wide significantly associated with Shannon diversity (p=3.2x10-8). We identified 117 DMRs associated with exacerbation‐related bacterial genera (Absconditabacteriales, Bifidobacterium, Capnocytophaga), and 126 DMRs with alpha diversity indices. Top‐hit DMRs were localized in major genes related to the histocompatibility complex (MHC) (PPP1R11: 14 CpGs, p=1.6x10-15; ATF6B: 33 CpGs, p=6.4x10-29; MPIG6B: 29 CpGs, p=2.1x10-31) and to a toll‐like receptor signaling gene (ZC3H12D: 13 CpGs, p=2.2x10-19). Enrichment analysis revealed overrepresentation of MHC protein complex genes (adjusted p=7.1x10-3).
Conclusion: Our findings showed novel associations between leukocyte DNAm at immune‐related loci and the salivary microbiome involved in asthma exacerbations, highlighting the role of the innate immune system in host-microbiome interactions.
Funding: Fundación DISA (009/2024), MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00).