Multi-omic approach associates blood methylome with bronchodilator drug response in pediatric asthma

Javier Perez-Garcia; Esther Herrera-Luis; Annie Li; Angel C Y Mak; Scott Huntsman; Sam S Oh; Jennifer R Elhawary; Celeste Eng; Kenneth B Beckman; Donglei Hu; Fabian Lorenzo-Diaz; Michael A Lenoir; Jose Rodriguez-Santana; Noah Zaitlen; Jesús Villar; Luisa N Borrell; Esteban G Burchard; Maria Pino-Yanes

doi:10.1016/j.jaci.2023.01.026

Multi-omic approach associates blood methylome with bronchodilator drug response in pediatric asthma

J Allergy Clin Immunol. 2023 Jun;151(6):1503-1512. doi: 10.1016/j.jaci.2023.01.026. Epub 2023 Feb 14.

Authors

Javier Perez-Garcia¹, Esther Herrera-Luis¹, Annie Li², Angel C Y Mak², Scott Huntsman², Sam S Oh², Jennifer R Elhawary², Celeste Eng², Kenneth B Beckman³, Donglei Hu², Fabian Lorenzo-Diaz⁴, Michael A Lenoir⁵, Jose Rodriguez-Santana⁶, Noah Zaitlen⁷, Jesús Villar⁸, Luisa N Borrell⁹, Esteban G Burchard¹⁰, Maria Pino-Yanes¹¹

Affiliations

¹ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain.
² Department of Medicine, University of California, San Francisco, Calif.
³ University of Minnesota Genomics Center, Minneapolis, Minn.
⁴ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain; Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), ULL, Santa Cruz de Tenerife, Spain.
⁵ Bay Area Pediatrics, Oakland, Calif.
⁶ Centro de Neumología Pediátrica, San Juan, Puerto Rico.
⁷ Department of Neurology, University of California, Los Angeles, Calif; Department of Computational Medicine, University of California, Los Angeles, Calif.
⁸ Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
⁹ Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, City University of New York, New York, NY.
¹⁰ Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
¹¹ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Tecnologías Biomédicas, ULL, La Laguna, Spain. Electronic address: mdelpino@ull.edu.es.

PMID: 36796456
DOI: 10.1016/j.jaci.2023.01.026

Abstract

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 is unknown.

Objective: This study aimed 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 (8-21 years old) with asthma 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. Machine learning was used to develop a panel of epigenetic markers to classify treatment response.

Results: We identified 5 differentially methylated regions and 2 CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, P = 6.8 × 10^-9) and DNASE2 (cg15341340, P = 7.8 × 10^-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 = 3.5 × 10^-3). Moreover, a panel of 70 CpGs showed good classification for those with response and nonresponse to albuterol therapy in African American and Latino children (area under the receiver operating characteristic curve for training, 0.99; for validation, 0.70-0.71). The DNA methylation model showed similar discrimination as clinical predictors (P > .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.

Keywords: African Americans; Epigenomics; Hispanic Americans; albuterol; precision medicine.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adolescent
Adult
Albuterol / therapeutic use
Asthma* / drug therapy
Asthma* / genetics
Asthma* / metabolism
Bronchodilator Agents* / therapeutic use
Child
DNA Methylation
Epigenome
Fibrinogen / metabolism
Genome-Wide Association Study
Humans
Multiomics
Young Adult

Substances

Bronchodilator Agents
Albuterol
FGL2 protein, human
Fibrinogen

Abstract

Publication types

MeSH terms

Substances

Grants and funding