Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

Elena Martin-Gonzalez; Javier Perez-Garcia; Esther Herrera-Luis; Mario Martin-Almeida; Simon Kebede-Merid; Natalia Hernandez-Pacheco; Fabian Lorenzo-Diaz; Ruperto González-Pérez; Olaia Sardón; José M. Hernández-Pérez; Paloma Poza-Guedes; Inmaculada Sánchez-Machín; Elena Mederos-Luis; Paula Corcuera; Leyre López-Fernández; Berta Román-Bernal; Antoaneta A. Toncheva; Susanne Harner; Christine Wolff; Susanne Brandstetter; Mahmoud Ibrahim Abdel-Aziz; Simone Hashimoto; Susanne J.H. Vijverberg; Aletta D. Kraneveld; Uroš Potočnik; Michael Kabesch; Anke H. Maitland-van der Zee; Jesús Villar; Erik Melén; Maria Pino-Yanes

doi:10.1111/all.16490

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

Elena Martin-Gonzalez, Javier Perez-Garcia, Esther Herrera-Luis, Mario Martin-Almeida, Simon Kebede-Merid, Natalia Hernandez-Pacheco, Fabian Lorenzo-Diaz, Ruperto González-Pérez, Olaia Sardón, José M. Hernández-Pérez, Paloma Poza-Guedes, Inmaculada Sánchez-Machín, Elena Mederos-Luis, Paula Corcuera, Leyre López-Fernández, Berta Román-Bernal, Antoaneta A. Toncheva, Susanne Harner, Christine Wolff, Susanne BrandstetterMahmoud Ibrahim Abdel-Aziz, Simone Hashimoto, Susanne J.H. Vijverberg, Aletta D. Kraneveld, Uroš Potočnik, Michael Kabesch, Anke H. Maitland-van der Zee, Jesús Villar, Erik Melén, Maria Pino-Yanes^*

^*Corresponding author for this work

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

Abstract

Background: Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. Objective: This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. Methods: DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10⁻⁸) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Results: Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality. Conclusions: DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

Original language	English
Pages (from-to)	1086-1099
Number of pages	14
Journal	Allergy: European Journal of Allergy and Clinical Immunology
Volume	80
Issue number	4
Early online date	5 Feb 2025
DOIs	https://doi.org/10.1111/all.16490
Publication status	Published - Apr 2025

Bibliographical note

Publisher Copyright:
© 2025 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Funding

This work was funded by grant PID2020\u2010116274RB\u2010I00 funded by MICIU/AEI/ 10.13039/501100011033 (Spanish Ministry of Science, Innovation, and Universities) and grant PIFIISC22/24 by Fundaci\u00F3n Canaria Instituto de Investigaci\u00F3n Sanitaria de Canarias (FIISC). This work was also partially funded by CIBER \u2010Consorcio Centro de Investigaci\u00F3n Biom\u00E9dica en Red\u2010 (CIBERES), Instituto de Salud Carlos III (ISCIII), and European Regional Development Fund (CB06/06/1088), European Academy of Allergy and Clinical Immunology (EAACI)\u2010Allergopharma Research Award 2021 to MP\u2010Y, Sociedad Espa\u00F1ola de Alergolog\u00EDa e Inmunolog\u00EDa Cl\u00EDnica (SEAIC) (grant A21_05 to RG\u2010P), and Sociedad Espa\u00F1ola de Neumolog\u00EDa y Cirug\u00EDa Tor\u00E1cica (SEPAR http://www.separ.es , award 1264\u20132022 to JMH\u2010P). The BAMSE study was funded by the Swedish Heart\u2010Lung Foundation, The Swedish Research Council, Region Stockholm (ALF), MeDALL (Mechanisms of the Development of ALLergy; European Union grant agreement No. 261357). 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\u201016\u2010500106); the German Ministry of Education and Research (BMBF) (project No. FKZ 031\u2009L0088); 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\u20101 Call. EM\u2010G and MM\u2010A were funded by a fellowship (TESIS2022010045 and FPI2024010123, respectively) co\u2010financed by the Canarian Agency for Research, Innovation and the Information Society of the Counseling of Universities, Science and Innovation and Culture and by the European Social Fund Plus (ESF+) Integrated Operational Program of the Canary Islands 2021\u20132027, Axis 3 Priority Theme 74 (85%). JP\u2010G was funded by fellowship FPU19/02175 (Formaci\u00F3n de Profesorado Universitario Program) from the MICIU. EH\u2010L was funded by fellowship PRE2018\u2010083837 from MICIU/AEI/ 10.13039/501100011033 and the European Social Fund \u201CInvesting in your future\u201D. NH\u2010P was supported with a Medium\u2010Term Research Fellowship by the EAACI and a Long\u2010Term Research Fellowship by the European Respiratory Society (ERS) (LTRF202101\u201000861). M.IA\u2010A was funded by the Egyptian Government Ph.D. Scholarships. UP was funded by the Slovenian Research and Innovation Agency (funding No. P3\u20100427, I0\u20100029, J3\u20104497). JVr was funded by Instituto de Salud Carlos III, Madrid, Spain (PI19/00141, AC21_2/00039), ERAPerMed (JTC_2021), the European Regional Development Funds, Fundaci\u00F3n Canaria Instituto de Investigaci\u00F3n Sanitaria de Canarias, Spain (PIFIISC21\u201036), and Asociaci\u00F3n Cient\u00EDfica Pulm\u00F3n y Ventilaci\u00F3n Mec\u00E1nica, Spain. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Funding: BAIAP2 CPNE6 CRNKL1 FKBP5 LOC100130691 PIWIL3 TMEM88B ZBTB16 E.M.\u2010G. and M.M.\u2010A. report a fellowship from the Canarian Agency for Research, Innovation, and the Information Society of the Counseling of Universities, Science and Innovation and Culture. J.P.\u2010G. reports a fellowship from the MICIU. E.H.\u2010L. reports a fellowship from MCIN and support from the National Institute of Health (NIH) National Human Genome Research Institute (NHGRI) (R35HG011944\u201002), outside the submitted work. N.H.\u2010P. reports fellowships from the European Academy of Allergy and Clinical Immunology and the European Respiratory Society (ERS), as well as lecture honoraria from OMNIPREX, S.L. outside of the submitted work. R.G.\u2010P. reports grants from Fundaci\u00F3n Canaria Instituto de Investigaci\u00F3n Sanitaria de Canarias (FIISC) (grant PIFIISC22/24) and from Sociedad Espa\u00F1ola de Alergolog\u00EDa e Inmunolog\u00EDa Cl\u00EDnica (SEAIC). J.M.H.\u2010P. reports grant 1264\u20102022 from Sociedad Espa\u00F1ola de Neumolog\u00EDa y Cirug\u00EDa Tor\u00E1cica (SEPAR http://www.separ.es ). A.H.M. is the PI of a public\u2010private consortium (P4O2 [Precision Medicine for More Oxygen]) sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (AbbVie, Boehringer Ingelheim, Breathomix, Fluidda, Ortec Logiqcare, PeXA, Philips, Quantib\u2010U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis, RespiQ). A.H.M. received money paid to the institution from the ZonMW grant long COVID, the Stichting TAAI research grant, the EUROSTARS research grant COPDetect, an unrestricted research grant from Boehringer Ingelheim, an unrestricted research grant from the Vertex Innovation Award, a Dutch Lung Foundation grant, a Stichting Asthma Bestrijding grant, and the Innovative Medicine Initiative (IMI) 3TR research grant. A.H.M. received consulting fees from Astra Zeneca and Boehringer Ingelheim and received an honorarium for a lecture from G.S.K. E.M. reports lecture and/or advisory board fees from ALK, AstraZeneca, Chiesi, and Sanofi outside the submitted study. J.V. and M.P.\u2010Y. report grants from the Instituto de Salud Carlos III, Madrid, Spain. M.P.\u2010Y. reports grants from MICIU/AEI/ 10.13039/501100011033 (Spanish Ministry of Science, Innovation, and Universities), FIISC, and EAACI. M.P.\u2010Y. also received grant support from CSL Behring for a project outside this work. The rest of the authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the article. No supporting institution may gain or lose financially through this publication.

Funders	Funder number
Ministerio de Ciencia, Innovación y Universidades
Boehringer Ingelheim España
Canarian Agency for Research, Innovation
MeDALL
Information Society of the Counseling of Universities, Science and Innovation and Culture
CSL Behring
Instituto de Salud Carlos III
Lung Foundation Netherlands
National Institutes of Health
Agencia Estatal de Investigación
European Academy of Allergy and Clinical Immunology
Asociación Científica Pulmón y Ventilación Mecánica
Canarian Agency for Research, Innovation and the Information Society of the Counseling of Universities, Science and Innovation and Culture
Innovative Medicines Initiative
Stichting Astma Bestrijding
Hjärt-Lungfonden
Vetenskapsrådet
The Slovenian Research and Innovation Agency	PI19/00141, AC21_2/00039, I0‐0029, P3‐0427, JTC_2021, J3‐4497
National Human Genome Research Institute	R35HG011944‐02
Sociedad Española de Alergología e Inmunología Clínica	A21_05
Fundación Canaria Instituto de Investigación Sanitaria de Canarias	PIFIISC21‐36, PIFIISC22/24
Bundesministerium für Bildung und Forschung	FKZ 031 L0088
European Commission	FPI2024010123, AC15/00015, 261357, AC15/00058, TESIS2022010045
Sociedad Española de Neumología y Cirugía Torácica	1264–2022
European Respiratory Society	LTRF202101‐00861
Ministry of Education, Science, and Sport of the Republic of Slovenia	C330‐16‐500106
European Social Fund Plus	FPU19/02175
ZonMw	9003035001
European Regional Development Fund	CB06/06/1088

Keywords

Asthma
epigenome-wide association study
epigenomics
Europeans
exacerbations

Access to Document

10.1111/all.16490

Cite this

Martin-Gonzalez, E., Perez-Garcia, J., Herrera-Luis, E., Martin-Almeida, M., Kebede-Merid, S., Hernandez-Pacheco, N., Lorenzo-Diaz, F., González-Pérez, R., Sardón, O., Hernández-Pérez, J. M., Poza-Guedes, P., Sánchez-Machín, I., Mederos-Luis, E., Corcuera, P., López-Fernández, L., Román-Bernal, B., Toncheva, A. A., Harner, S., Wolff, C., ... Pino-Yanes, M. (2025). Epigenome-Wide Association Study of Asthma Exacerbations in Europeans. Allergy: European Journal of Allergy and Clinical Immunology, 80(4), 1086-1099. https://doi.org/10.1111/all.16490

@article{1609e26265f847829cd18c7bcf4a49da,

title = "Epigenome-Wide Association Study of Asthma Exacerbations in Europeans",

abstract = "Background: Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. Objective: This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. Methods: DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10−8) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Results: Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality. Conclusions: DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.",

keywords = "Asthma, epigenome-wide association study, epigenomics, Europeans, exacerbations",

author = "Elena Martin-Gonzalez and Javier Perez-Garcia and Esther Herrera-Luis and Mario Martin-Almeida and Simon Kebede-Merid and Natalia Hernandez-Pacheco and Fabian Lorenzo-Diaz and Ruperto Gonz{\'a}lez-P{\'e}rez and Olaia Sard{\'o}n and Hern{\'a}ndez-P{\'e}rez, {Jos{\'e} M.} and Paloma Poza-Guedes and Inmaculada S{\'a}nchez-Mach{\'i}n and Elena Mederos-Luis and Paula Corcuera and Leyre L{\'o}pez-Fern{\'a}ndez and Berta Rom{\'a}n-Bernal and Toncheva, {Antoaneta A.} and Susanne Harner and Christine Wolff and Susanne Brandstetter and Abdel-Aziz, {Mahmoud Ibrahim} and Simone Hashimoto and Vijverberg, {Susanne J.H.} and Kraneveld, {Aletta D.} and Uro{\v s} Poto{\v c}nik and Michael Kabesch and {Maitland-van der Zee}, {Anke H.} and Jes{\'u}s Villar and Erik Mel{\'e}n and Maria Pino-Yanes",

note = "Publisher Copyright: {\textcopyright} 2025 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.",

year = "2025",

month = apr,

doi = "10.1111/all.16490",

language = "English",

volume = "80",

pages = "1086--1099",

journal = "Allergy: European Journal of Allergy and Clinical Immunology",

issn = "0105-4538",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

}

Martin-Gonzalez, E, Perez-Garcia, J, Herrera-Luis, E, Martin-Almeida, M, Kebede-Merid, S, Hernandez-Pacheco, N, Lorenzo-Diaz, F, González-Pérez, R, Sardón, O, Hernández-Pérez, JM, Poza-Guedes, P, Sánchez-Machín, I, Mederos-Luis, E, Corcuera, P, López-Fernández, L, Román-Bernal, B, Toncheva, AA, Harner, S, Wolff, C, Brandstetter, S, Abdel-Aziz, MI, Hashimoto, S, Vijverberg, SJH, Kraneveld, AD, Potočnik, U, Kabesch, M, Maitland-van der Zee, AH, Villar, J, Melén, E & Pino-Yanes, M 2025, 'Epigenome-Wide Association Study of Asthma Exacerbations in Europeans', Allergy: European Journal of Allergy and Clinical Immunology, vol. 80, no. 4, pp. 1086-1099. https://doi.org/10.1111/all.16490

TY - JOUR

T1 - Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

AU - Martin-Gonzalez, Elena

AU - Perez-Garcia, Javier

AU - Herrera-Luis, Esther

AU - Martin-Almeida, Mario

AU - Kebede-Merid, Simon

AU - Hernandez-Pacheco, Natalia

AU - Lorenzo-Diaz, Fabian

AU - González-Pérez, Ruperto

AU - Sardón, Olaia

AU - Hernández-Pérez, José M.

AU - Poza-Guedes, Paloma

AU - Sánchez-Machín, Inmaculada

AU - Mederos-Luis, Elena

AU - Corcuera, Paula

AU - López-Fernández, Leyre

AU - Román-Bernal, Berta

AU - Toncheva, Antoaneta A.

AU - Harner, Susanne

AU - Wolff, Christine

AU - Brandstetter, Susanne

AU - Abdel-Aziz, Mahmoud Ibrahim

AU - Hashimoto, Simone

AU - Vijverberg, Susanne J.H.

AU - Kraneveld, Aletta D.

AU - Potočnik, Uroš

AU - Kabesch, Michael

AU - Maitland-van der Zee, Anke H.

AU - Villar, Jesús

AU - Melén, Erik

AU - Pino-Yanes, Maria

PY - 2025/4

Y1 - 2025/4

N2 - Background: Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. Objective: This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. Methods: DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10−8) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Results: Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality. Conclusions: DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

AB - Background: Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. Objective: This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. Methods: DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10−8) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Results: Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality. Conclusions: DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

KW - Asthma

KW - epigenome-wide association study

KW - epigenomics

KW - Europeans

KW - exacerbations

UR - http://www.scopus.com/inward/record.url?scp=85217011663&partnerID=8YFLogxK

U2 - 10.1111/all.16490

DO - 10.1111/all.16490

M3 - Article

AN - SCOPUS:85217011663

SN - 0105-4538

VL - 80

SP - 1086

EP - 1099

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

IS - 4

ER -

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans

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