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. 2025 Apr;80(4):1086-1099.
doi: 10.1111/all.16490. Epub 2025 Feb 5.

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

Elena Martin-Gonzalez  1 , Javier Perez-Garcia  1 , Esther Herrera-Luis  2 , Mario Martin-Almeida  1 , Simon Kebede-Merid  3 , Natalia Hernandez-Pacheco  3 , Fabian Lorenzo-Diaz  1   4 , Ruperto González-Pérez  5   6 , Olaia Sardón  7   8 , José M Hernández-Pérez  9   10 , Paloma Poza-Guedes  5   6 , Inmaculada Sánchez-Machín  5 , Elena Mederos-Luis  5 , Paula Corcuera  7 , Leyre López-Fernández  7 , Berta Román-Bernal  11 , Antoaneta A Toncheva  12 , Susanne Harner  12 , Christine Wolff  12 , Susanne Brandstetter  12 , Mahmoud Ibrahim Abdel-Aziz  13   14 , Simone Hashimoto  13   15 , Susanne J H Vijverberg  13 , Aletta D Kraneveld  16 , Uroš Potočnik  17   18   19 , Michael Kabesch  20   21 , Anke H Maitland-van der Zee  13   15 , Jesús Villar  22   23   24   25 , Erik Melén  3 , Maria Pino-Yanes  1   22   26
Affiliations

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

Elena Martin-Gonzalez et al. Allergy. 2025 Apr.

Abstract

Background: Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered.

Objective: This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans.

Methods: DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10-8) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted.

Results: Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality.

Conclusions: DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

Keywords: Asthma; Europeans; epigenome‐wide association study; epigenomics; exacerbations.

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