{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:20:17Z","timestamp":1791523217160,"version":"4.3.4"},"posted":{"date-parts":[[2026,4,18]]},"group-title":"Allergy and Immunology","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Extreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (\n                    <jats:italic>p<\/jats:italic>\n                    &lt;9x10\n                    <jats:sup>-8<\/jats:sup>\n                    , \u03bb=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by \u22651 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.16.26350345","type":"posted-content","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T20:45:11Z","timestamp":1776545111000},"source":"Crossref","is-referenced-by-count":1,"title":["Multi-Ancestry Epigenome-Wide Meta-Analysis Identifies Novel Bulk and Cell-Type-Specific Epigenetic Markers of Asthma with Severe Exacerbations"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7813-4381","authenticated-orcid":false,"given":"Javier","family":"Perez-Garcia","sequence":"first","affiliation":[{"name":"Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain"},{"name":"Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3522-3103","authenticated-orcid":false,"given":"Elena","family":"Martin-Gonzalez","sequence":"additional","affiliation":[{"name":"Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain"},{"name":"Instituto de Tecnolog\u00edas Biom\u00e9dicas (ITB), Universidad de La 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