Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma

Mario Martin-Almeida, Javier Perez-Garcia, Esther Herrera-Luis, Carlos Rosa-Baez, Mario Gorenjak, Anne H. Neerincx, Olaia Sardón-Prado, Antoaneta A. Toncheva, Susanne Harner, Christine Wolff, Susanne Brandstetter, Elisa Valletta, Mahmoud I. Abdel-Aziz, Simone Hashimoto, Vojko Berce, Paula Corcuera-Elosegui, Javier Korta-Murua, Heike Buntrock-Döpke, Susanne J. H. Vijverberg, Joris VersterNikki Kerssemakers, Anna Hedman, Catarina Almqvist, Jesús Villar, Aletta Kraneveld, Uroš Potočnik, Michael Kabesch, Anke Maitland-van der Zee, Maria Pino-Yanes, on behalf of the SysPharmPediA Consortium

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Abstract

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.

Original languageEnglish
Article number676
Number of pages15
JournalBiomedicines
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 2023

Bibliographical note

Funding Information:
This study was funded by the Spanish Ministry of Science and Innovation (MCIN), grant PID2020-116274RB-I00 awarded by MCIN/AEI/10.13039/501100011033. The SysPharmPediA consortium was supported by ZonMW [project No. 9003035001], the Ministry of Education, Science, and Sport of the Republic of Slovenia [contract No. C330-16-500106]; the German Ministry of Education and Research (BMBF) [project No. FKZ 031L0088]; Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Program framework [award No. AC15/00015 and AC15/00058] under the frame of the ERACoSysMed JTC-1 Call. M.P.-Y. was supported by a grant from the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”. J.P.-G. was funded by the fellowship FPU19/02175 (Formación Profesorado Universitario Program) from the Spanish Ministry of Universities. E.H.-L. was funded by fellowship PRE2018-083837 from MCIN/AEI/10.13039/501100011033 and the European Social Fund “Investing in your future”. M.P.-Y. and J.V. were also supported by CIBER—Consorcio Centro de Investigación Biomédica en Red—(CIBERES), Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and Unión Europea—European Regional Development Fund (CB06/06/1088). U.P., V.B., and M.G. were funded by Slovenian Research Agency (research core funding No. P3-0427). M.I.A.-A. was funded by the Egyptian Government Ph.D. Scholarships. The STOPPA study was funded by the Swedish Research Council project grant 2018-02640 and the Swedish Asthma and Allergy Research Foundation.

Publisher Copyright:
© 2023 by the authors.

Keywords

  • epigenetic
  • biomarker
  • methylation
  • asthma
  • FeNO
  • BDR
  • precision medicine

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