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

doi:10.3390/biomedicines11030676

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 VersterNikki 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

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Article number	676
Pages (from-to)	1-15
Number of pages	15
Journal	Biomedicines
Volume	11
Issue number	3
Early online date	23 Feb 2023
DOIs	https://doi.org/10.3390/biomedicines11030676
Publication status	Published - Mar 2023
Externally published	Yes

Bibliographical note

This article belongs to the Special Issue Recent Advances in Asthma Research in a Multiomics Era

Funding

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.

Funders	Funder number
Consorcio Centro de Investigación Biomédica en Red—
Ministerio de Ciencia e Innovación and Unión Europea
Ministry of Education, Science, and Sport of the Republic of Slovenia	C330-16-500106
Ramón y Cajal Program	RYC-2015-17205
Spanish Ministry of Universities	PRE2018-083837
Swedish Asthma and Allergy Research Foundation
Center for International Business Education and Research, University of Illinois at Urbana-Champaign
European Commission	AC15/00015, AC15/00058
European Commission
ZonMw	9003035001
ZonMw
Bundesministerium für Bildung und Forschung	FKZ 031L0088
Bundesministerium für Bildung und Forschung
Javna Agencija za Raziskovalno Dejavnost RS	P3-0427
Javna Agencija za Raziskovalno Dejavnost RS
Vetenskapsrådet	2018-02640
Vetenskapsrådet
Instituto de Salud Carlos III
Ministerio de Ciencia e Innovación	MCIN/AEI/10.13039/501100011033, PID2020-116274RB-I00
Ministerio de Ciencia e Innovación
European Social Fund	FPU19/02175
European Social Fund
European Regional Development Fund	CB06/06/1088
European Regional Development Fund

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Martin-Almeida, M., Perez-Garcia, J., Herrera-Luis, E., Rosa-Baez, C., Gorenjak, M., Neerincx, A. H., Sardón-Prado, O., Toncheva, A. A., Harner, S., Wolff, C., Brandstetter, S., Valletta, E., Abdel-Aziz, M. I., Hashimoto, S., Berce, V., Corcuera-Elosegui, P., Korta-Murua, J., Buntrock-Döpke, H., Vijverberg, S. J. H., ... On Behalf Of The SysPharmPediA Consortium (2023). Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma. Biomedicines, 11(3), 1-15. Article 676. https://doi.org/10.3390/biomedicines11030676

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

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. ",

author = "Mario Martin-Almeida and Javier Perez-Garcia and Esther Herrera-Luis and Carlos Rosa-Baez and Mario Gorenjak and Neerincx, \{Anne H\} and Olaia Sard{\'o}n-Prado and Toncheva, \{Antoaneta A\} and Susanne Harner and Christine Wolff and Susanne Brandstetter and Elisa Valletta and Abdel-Aziz, \{Mahmoud I\} and Simone Hashimoto and Vojko Berce and Paula Corcuera-Elosegui and Javier Korta-Murua and Heike Buntrock-D{\"o}pke and Vijverberg, \{Susanne J H\} and Verster, \{Joris C\} and Nikki Kerssemakers and Hedman, \{Anna M\} and Catarina Almqvist and Jes{\'u}s Villar and Kraneveld, \{Aletta D\} and Uro{\v s} Poto{\v c}nik and Michael Kabesch and Zee, \{Anke H Maitland-van der\} and Maria Pino-Yanes and \{On Behalf Of The SysPharmPediA Consortium\}",

note = "This article belongs to the Special Issue Recent Advances in Asthma Research in a Multiomics Era",

year = "2023",

month = mar,

doi = "10.3390/biomedicines11030676",

language = "English",

volume = "11",

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Martin-Almeida, M, Perez-Garcia, J, Herrera-Luis, E, Rosa-Baez, C, Gorenjak, M, Neerincx, AH, Sardón-Prado, O, Toncheva, AA, Harner, S, Wolff, C, Brandstetter, S, Valletta, E, Abdel-Aziz, MI, Hashimoto, S, Berce, V, Corcuera-Elosegui, P, Korta-Murua, J, Buntrock-Döpke, H, Vijverberg, SJH, Verster, JC, Kerssemakers, N, Hedman, AM, Almqvist, C, Villar, J, Kraneveld, AD, Potočnik, U, Kabesch, M, Zee, AHMD, Pino-Yanes, M & On Behalf Of The SysPharmPediA Consortium 2023, 'Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma', Biomedicines, vol. 11, no. 3, 676, pp. 1-15. https://doi.org/10.3390/biomedicines11030676

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T1 - Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma

AU - Martin-Almeida, Mario

AU - Perez-Garcia, Javier

AU - Herrera-Luis, Esther

AU - Rosa-Baez, Carlos

AU - Gorenjak, Mario

AU - Neerincx, Anne H

AU - Sardón-Prado, Olaia

AU - Toncheva, Antoaneta A

AU - Harner, Susanne

AU - Wolff, Christine

AU - Brandstetter, Susanne

AU - Valletta, Elisa

AU - Abdel-Aziz, Mahmoud I

AU - Hashimoto, Simone

AU - Berce, Vojko

AU - Corcuera-Elosegui, Paula

AU - Korta-Murua, Javier

AU - Buntrock-Döpke, Heike

AU - Vijverberg, Susanne J H

AU - Verster, Joris C

AU - Kerssemakers, Nikki

AU - Hedman, Anna M

AU - Almqvist, Catarina

AU - Villar, Jesús

AU - Kraneveld, Aletta D

AU - Potočnik, Uroš

AU - Kabesch, Michael

AU - Zee, Anke H Maitland-van der

AU - Pino-Yanes, Maria

AU - On Behalf Of The SysPharmPediA Consortium, null

N1 - This article belongs to the Special Issue Recent Advances in Asthma Research in a Multiomics Era

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

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

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