B17-01 Multi-Ancestry Meta-Ewas Identifies Novel Associations of Epigenetic Markers, Methylation-Predicted Proteins, and Lung Aging With Asthma With Severe Exacerbations

Abstract Rationale Asthma is the most common chronic pediatric disease, and its exacerbations contribute significantly to the global disease burden. Asthma disparities across populations result from gene-environment interactions, which may be captured by DNA methylation (DNAm), mostly in blood and airway tissue. The role of DNAm in asthma exacerbations remains understudied, and extreme phenotype comparisons yielding insights in genetic studies have not been explored in epigenome-wide association studies (EWAS). We aimed to identify leukocyte DNAm markers of asthma with severe exacerbations across diverse ancestries. Methods We performed a meta-EWAS of asthma with exacerbations in 502 African American (SAGE), 466 Puerto Rican, and 224 Mexican American youth (GALA II) (8-21 years), comparing controls without asthma and asthma cases with severe exacerbations (NDiscovery=1,192). We analyzed 700.000 CpGs (MethylationEPICv1 array) while correcting for age, sex, ancestry, blood cell heterogeneity, and batch. We corrected genomic inflation using a Bayesian method, and genome-wide significance was declared at p9x10-8. Replication was performed in an independent meta-EWAS (NReplication=1,553) across different ancestry groups, including European descendants, non-White Hispanics, and other groups (Project Viva, GEMAS, GALA II 450K). We evaluated blood signals in nasal epithelia from 392 children (Project Viva). We analyzed differentially methylated regions (DMRs), 109 DNAm-predicted plasma proteins, and 11 physiological systems aging clocks (SystemsAge). Significance was declared using a false discovery rate (FDR)0.05. Results We identified 505 CpGs genome-wide significantly associated with asthma and exacerbations in the discovery phase (Figure 1, λ = 1.05). We replicated 29 CpGs, of which 9 CpGs were identified in nasal epithelia (p0.05). These were annotated to genes involved in bronchodilation (ADRB2), immunity (CCL18, PIK3AP1, LPIN2, TRIM33), airway inflammation (ADAM8), and ubiquitin-specific processing (USP1 and ASB6). We found 119 DMRs involved in Th1/Th2 inflammation (IL18RAP, TNFRSF4, TNFRSF1A, TBX1, BACH2), chemokine signaling (CCL4, CX3RC1), and airway remodeling (GATA6). Furthermore, 21 DNAm-predicted plasma proteins were associated with severe asthma (FDR0.05), implicated in inflammation (SERPINA3, CCL2, IL-19, Complement C5a, and C9), airway remodeling (MMP-1), tissue injury, and host defense (Granzyme A, Granulysin). Asthma with exacerbations was associated with a lower DNAm-clock score predictive of lung aging (FDR0.05). Conclusions In the first meta-EWAS of asthma with severe exacerbations to date, we discovered novel associations of DNAm loci involved in immune response and airway remodeling, multiple DNAm-predicted plasma proteins, and a lung aging biomarker. Our study provides novel insights into potential biomarkers and therapeutic targets for asthma exacerbations. This abstract is funded by: NHLBI (5R01HL117004-06, 1R01HL155024-01); NHGRI; NIEHS (R01 ES031259); NIMHD; MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00, PID2024-160302OB-I00); Catalina Ruiz Program (ACIISI).