Biomedicines (Feb 2023)
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 C. Verster,
- Nikki Kerssemakers,
- Anna M Hedman,
- Catarina Almqvist,
- Jesús Villar,
- Aletta D. Kraneveld,
- Uroš Potočnik,
- Michael Kabesch,
- Anke H. Maitland-van der Zee,
- Maria Pino-Yanes,
- on behalf of the SysPharmPediA Consortium
Affiliations
- Mario Martin-Almeida
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain
- Javier Perez-Garcia
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain
- Esther Herrera-Luis
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain
- Carlos Rosa-Baez
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain
- Mario Gorenjak
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Anne H. Neerincx
- Department of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Olaia Sardón-Prado
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, Spain
- Antoaneta A. Toncheva
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Susanne Harner
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Christine Wolff
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Susanne Brandstetter
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Elisa Valletta
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Mahmoud I. Abdel-Aziz
- Department of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Simone Hashimoto
- Department of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Vojko Berce
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Paula Corcuera-Elosegui
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, Spain
- Javier Korta-Murua
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, Spain
- Heike Buntrock-Döpke
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Susanne J. H. Vijverberg
- Department of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Joris C. Verster
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands
- Nikki Kerssemakers
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands
- Anna M Hedman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, 171 77 Stockholm, Sweden
- Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, 171 77 Stockholm, Sweden
- Jesús Villar
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands
- Uroš Potočnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Michael Kabesch
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, D-93049 Regensburg, Germany
- Anke H. Maitland-van der Zee
- Department of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Maria Pino-Yanes
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain
- on behalf of the SysPharmPediA Consortium
- DOI
- https://doi.org/10.3390/biomedicines11030676
- Journal volume & issue
-
Vol. 11,
no. 3
p. 676
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) p −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.
Keywords
