In The Journal of allergy and clinical immunology
BACKGROUND : Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation (DNAm) is unknown.
OBJECTIVE : This study aims to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden.
METHODS : We studied 414 children and young adults asthma patients (8-21 years old) in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Furthermore, a machine learning approach was used to develop a panel of epigenetic markers to classify treatment response.
RESULTS : We identified five differentially methylated regions and two CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, p=6.8x10-9) and DNASE2 (cg15341340, p=7.8x10-8), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate<0.05). The CpG cg15341340 was replicated in Latinos (p=3.5x10-3). Moreover, a panel of 70 CpGs showed good classification for albuterol responders and nonresponders in African American and Latino children (AUCtraining:0.99, AUCvalidation:0.70-0.71). DNAm model showed similar discrimination as clinical predictors (p>0.05).
CONCLUSIONS : We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases.
Perez-Garcia Javier, Herrera-Luis Esther, Li Annie, Mak Angel C Y, Huntsman Scott, Oh Sam S, Elhawary Jennifer R, Eng Celeste, Beckman Kenneth B, Hu Donglei, Lorenzo-Diaz Fabian, Lenoir Michael A, Rodriguez-Santana Jose, Zaitlen Noah, Villar Jesús, Borrell Luisa N, Burchard Esteban G, Pino-Yanes Maria
2023-Feb-14
African Americans, Albuterol, Epigenomics, Hispanic Americans, Precision Medicine
