Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth

Esther Herrera-Luis; Carlos Rosa-Baez; Scott Huntsman; Celeste Eng; Kenneth B Beckman; Michael A LeNoir; Jose R Rodriguez-Santana; Jesús Villar; Catherine Laprise; Luisa N Borrell; Elad Ziv; Esteban G Burchard; Maria Pino-Yanes

doi:10.1183/13993003.00714-2023

Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth

Eur Respir J. 2023 Dec 21;62(6):2300714. doi: 10.1183/13993003.00714-2023. Print 2023 Dec.

Authors

Esther Herrera-Luis^{1

2}, Carlos Rosa-Baez¹, Scott Huntsman³, Celeste Eng³, Kenneth B Beckman⁴, Michael A LeNoir^{1

5}, Jose R Rodriguez-Santana^{1

6}, Jesús Villar^{7

8

9}, Catherine Laprise^{10

11}, Luisa N Borrell¹², Elad Ziv^{13

14}, Esteban G Burchard^{3

14

15}, Maria Pino-Yanes^{16

8

15

17}

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 Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴ University of Minnesota Genomics Center, Minneapolis, MN, USA.
⁵ Bay Area Pediatrics, Oakland, CA, USA.
⁶ Centro de Neumología Pediátrica, San Juan, Puerto Rico.
⁷ Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
⁸ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
⁹ Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, ON, Canada.
¹⁰ Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Saguenay, QC, Canada.
¹¹ Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, QC, Canada.
¹² Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA.
¹³ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Division of General Internal Medicine, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Instituto de Tecnologías Biomédicas, Universidad de La Laguna (ULL), La Laguna, Spain.
¹⁶ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain mdelpino@ull.edu.es.
¹⁷ These authors contributed equally as senior authors.

Abstract

Background: The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences.

Methods: DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants.

Results: 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 (NCOR2) and cg16412914 (AXIN1) as asthma DNAm markers. Significant DNAm markers were enriched in previous associations for asthma, fractional exhaled nitric oxide, bacterial infections, immune regulation or eosinophilia. Functional annotation highlighted epigenetically regulated gene networks involved in corticosteroid response, host defence and immune regulation. Several implicated genes are targets for approved or experimental drugs, including TNNC1 and NDUFA12. Many differentially methylated loci previously associated with asthma were validated in our study.

Conclusions: We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations.

Publication types

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

MeSH terms

Adolescent
Asthma* / genetics
Child
DNA Methylation
Epigenesis, Genetic
Epigenome*
Gene Expression Profiling
Humans
NADPH Dehydrogenase / genetics

Substances

NDUFA12 protein, human
NADPH Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding