Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma
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....
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MDPI AG
2023-02-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Mario Martin-Almeida |
| collection | DOAJ |
| description | 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 <i>p</i> < 9 × 10<sup>−8</sup> were used to control for false-positive results. The CpG cg12835256 (<i>PLA2G12A</i>) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, <i>p</i> = 2.53 × 10<sup>−9</sup>) and nominally associated in nasal samples (coefficient = −0.015, <i>p</i> = 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. |
| first_indexed | 2024-03-11T06:54:24Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T06:54:24Z |
| publishDate | 2023-02-01 |
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| series | Biomedicines |
| spelling | doaj.art-48042b64d2f44f07b4cb43380a25ef952023-11-17T09:43:58ZengMDPI AGBiomedicines2227-90592023-02-0111367610.3390/biomedicines11030676Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric AsthmaMario Martin-Almeida0Javier Perez-Garcia1Esther Herrera-Luis2Carlos Rosa-Baez3Mario Gorenjak4Anne H. Neerincx5Olaia Sardón-Prado6Antoaneta A. Toncheva7Susanne Harner8Christine Wolff9Susanne Brandstetter10Elisa Valletta11Mahmoud I. Abdel-Aziz12Simone Hashimoto13Vojko Berce14Paula Corcuera-Elosegui15Javier Korta-Murua16Heike Buntrock-Döpke17Susanne J. H. Vijverberg18Joris C. Verster19Nikki Kerssemakers20Anna M Hedman21Catarina Almqvist22Jesús Villar23Aletta D. Kraneveld24Uroš Potočnik25Michael Kabesch26Anke H. Maitland-van der Zee27Maria Pino-Yanes28on behalf of the SysPharmPediA ConsortiumGenomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, SpainGenomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, SpainGenomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, SpainGenomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, SpainCenter for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, SloveniaDepartment of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDivision of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, SpainDepartment 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, GermanyDepartment 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, GermanyDepartment 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, GermanyDepartment 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, GermanyDepartment 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, GermanyDepartment of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsCenter for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, SloveniaDivision of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, SpainDivision of Pediatric Respiratory Medicine, Donostia University Hospital, 20014 San Sebastián, SpainDepartment 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, GermanyDepartment of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The NetherlandsDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, 171 77 Stockholm, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, 171 77 Stockholm, SwedenCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, SpainDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The NetherlandsCenter for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, SloveniaDepartment 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, GermanyDepartment of Respiratory Medicine, Amsterdam University Medical Centres—Loc. AMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsGenomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, SpainAsthma 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 <i>p</i> < 9 × 10<sup>−8</sup> were used to control for false-positive results. The CpG cg12835256 (<i>PLA2G12A</i>) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, <i>p</i> = 2.53 × 10<sup>−9</sup>) and nominally associated in nasal samples (coefficient = −0.015, <i>p</i> = 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.https://www.mdpi.com/2227-9059/11/3/676epigeneticbiomarkermethylationasthmaFeNOBDR |
| spellingShingle | 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 Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma Biomedicines epigenetic biomarker methylation asthma FeNO BDR |
| title | Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma |
| title_full | Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma |
| title_fullStr | Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma |
| title_full_unstemmed | Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma |
| title_short | Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma |
| title_sort | epigenome wide association studies of the fractional exhaled nitric oxide and bronchodilator drug response in moderate to severe pediatric asthma |
| topic | epigenetic biomarker methylation asthma FeNO BDR |
| url | https://www.mdpi.com/2227-9059/11/3/676 |
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