medRxiv : the preprint server for health sciences · 2026
Multi-Ancestry Epigenome-Wide Meta-Analysis Identifies Novel Bulk and Cell-Type-Specific Epigenetic Markers of Asthma with Severe Exacerbations.
СтатьяПрепринтНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Perez-Garcia Javier, Martin-Gonzalez Elena, Chen Zeyuan Johnson, Martin-Almeida Mario, Witonsky Jonathan, Gorla Aditya, Eng Celeste, Lorenzo-Diaz Fabian, Bozack Anne K, Elhawary Jennifer R, Hu Donglei, Huntsman Scott, González-Pérez Ruperto, Hernández-Pérez José M, Poza-Guedes Paloma, Mederos-Luis Elena, Sánchez-Machín Inmaculada, Rodriguez-Santana Jose, Villar Jesús, Rifas-Shiman Sheryl L, Hivert Marie-France, Oken Emily, Gold Diane R, Ziv Elad, Rahmani Elior, Burchard Esteban G, Cardenas Andres, Pino-Yanes Maria
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p <9x10-8, λ=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 > 1 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p <9x10-8, λ=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 > 1 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.
CONCLUSIONS: 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.