Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study

Background: most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients dev...

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Autores: Dávalos, Verónica, García-Prieto, Carlos A., Ferrer, Gerardo, Aguilera-Albesa, Sergio, Valencia-Ramos, Juan, Rodríguez-Palmero, Agustí, Ruiz, Montserrat, Planas-Serra, Laura, Jordán, Iolanda, Alegría, Iosune, Flores-Pérez, Patricia, Cantarín, Verónica, Fumadó, Verónica, Viadero Ubierna, María Teresa, Rodrigo, Carlos, Méndez-Hernández, María, López-Granados, Eduardo, Colobran, Roger, Rivière, Jacques G., Soler-Palacín, Pere
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/34487
Acceso en línea:https://hdl.handle.net/10902/34487
Access Level:acceso abierto
Palabra clave:Multisystem inflammatory syndrome in children
COVID-19
Kawasaki disease
Epigenetics
DNA methylation
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spelling Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective studyDávalos, VerónicaGarcía-Prieto, Carlos A.Ferrer, GerardoAguilera-Albesa, SergioValencia-Ramos, JuanRodríguez-Palmero, AgustíRuiz, MontserratPlanas-Serra, LauraJordán, IolandaAlegría, IosuneFlores-Pérez, PatriciaCantarín, VerónicaFumadó, VerónicaViadero Ubierna, María TeresaRodrigo, CarlosMéndez-Hernández, MaríaLópez-Granados, EduardoColobran, RogerRivière, Jacques G.Soler-Palacín, PereMultisystem inflammatory syndrome in childrenCOVID-19Kawasaki diseaseEpigeneticsDNA methylationBackground: most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MISC = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: the DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: we have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.Funding: Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya. Acknowledgements: We thank the Health Department and the Centres de Recerca de Catalunya (CERCA) Programme of the Generalitat de Catalunya, the Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3 and the Cellex Foundation for institutional support. We also wish to thank all the patients, family members and staff from all the units that participated in the study.ElsevierUniversidad de Cantabria20222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/34487eClinicalMedicine, 2022, 50, 101515reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/344872026-06-02T12:39:31Z
dc.title.none.fl_str_mv Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
title Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
spellingShingle Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
Dávalos, Verónica
Multisystem inflammatory syndrome in children
COVID-19
Kawasaki disease
Epigenetics
DNA methylation
title_short Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
title_full Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
title_fullStr Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
title_full_unstemmed Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
title_sort Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): a multicenter, retrospective study
dc.creator.none.fl_str_mv Dávalos, Verónica
García-Prieto, Carlos A.
Ferrer, Gerardo
Aguilera-Albesa, Sergio
Valencia-Ramos, Juan
Rodríguez-Palmero, Agustí
Ruiz, Montserrat
Planas-Serra, Laura
Jordán, Iolanda
Alegría, Iosune
Flores-Pérez, Patricia
Cantarín, Verónica
Fumadó, Verónica
Viadero Ubierna, María Teresa
Rodrigo, Carlos
Méndez-Hernández, María
López-Granados, Eduardo
Colobran, Roger
Rivière, Jacques G.
Soler-Palacín, Pere
author Dávalos, Verónica
author_facet Dávalos, Verónica
García-Prieto, Carlos A.
Ferrer, Gerardo
Aguilera-Albesa, Sergio
Valencia-Ramos, Juan
Rodríguez-Palmero, Agustí
Ruiz, Montserrat
Planas-Serra, Laura
Jordán, Iolanda
Alegría, Iosune
Flores-Pérez, Patricia
Cantarín, Verónica
Fumadó, Verónica
Viadero Ubierna, María Teresa
Rodrigo, Carlos
Méndez-Hernández, María
López-Granados, Eduardo
Colobran, Roger
Rivière, Jacques G.
Soler-Palacín, Pere
author_role author
author2 García-Prieto, Carlos A.
Ferrer, Gerardo
Aguilera-Albesa, Sergio
Valencia-Ramos, Juan
Rodríguez-Palmero, Agustí
Ruiz, Montserrat
Planas-Serra, Laura
Jordán, Iolanda
Alegría, Iosune
Flores-Pérez, Patricia
Cantarín, Verónica
Fumadó, Verónica
Viadero Ubierna, María Teresa
Rodrigo, Carlos
Méndez-Hernández, María
López-Granados, Eduardo
Colobran, Roger
Rivière, Jacques G.
Soler-Palacín, Pere
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv Multisystem inflammatory syndrome in children
COVID-19
Kawasaki disease
Epigenetics
DNA methylation
topic Multisystem inflammatory syndrome in children
COVID-19
Kawasaki disease
Epigenetics
DNA methylation
description Background: most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MISC = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: the DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: we have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/34487
url https://hdl.handle.net/10902/34487
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv eClinicalMedicine, 2022, 50, 101515
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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