Nasal Epigenome-Wide Association Study of Respiratory and Allergic Biomarkers in Mexican American Young Adults

Background: Mexican Americans have low asthma prevalence, but they experience a disproportionate clinical asthma burden. Nasal DNA methylation (DNAm) is a biomarker of airway diseases, but its relevance in young adult Mexican Americans and links to air pollution are underexplored. Objective: To identify nasal DNAm markers associated with asthma, allergic sensitization, fractional exhaled nitric oxide (FeNO), and lung function and evaluate associations with air pollution. Methods: We tested associations between nasal DNAm at 804,220 CpGs (EPICv2) and respiratory outcomes in 354 young adults from CHAMACOS (age 22) and evaluated replication in 540 adolescents from Project Viva (age 13). Epigenome-wide association studies were adjusted for confounders, and significance was declared at a false discovery rate (FDR)<0.05. Significant CpGs were evaluated for association with prenatal and past-year PM2.5 and O3 exposures, and with gene expression and genetic variation (in silico). We examined differentially methylated regions (DMRs), gene-set enrichments, and epigenetic aging. Results: We identified 49 CpGs associated with FeNO and 557 DMRs across multiple respiratory outcomes (FDR<0.05). Twenty-six CpGs and 103 DMRs associated with FeNO, asthma, and FEV1/FVC were replicated (e.g., LRRFIP1, PCSK6, EPX, IL13). Ten FeNO-related CpGs were associated with PM2.5 and/or O3 exposures (p<0.05) and 15 CpGs with nasal epithelial expression. We found enrichment for associations with respiratory/allergic biomarkers, obesity, smoking, longevity, asthma-related pathways (PI3K-AKT, TNF-α, IL-2), inflammatory transcription factors, and candidate asthma drugs. FeNO was associated with greater epigenetic aging acceleration (β=0.3, p=0.008). Conclusions: We identified nasal DNAm markers implicated in airway epithelial integrity and immune response predominantly associated with FeNO.