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

EClinicalMedicine

Juan Valencia-Ramos¹  Verónica Cantarín²  Iolanda Jordan²  Maria Teresa Viadero²  Iosune Alegría³  Gerardo Ferrer⁴  Manel Esteller⁵  Aurora Pujol⁵  Veronica Davalos⁶  Carlos A. García-Prieto⁶  Sergio Aguilera-Albesa⁶  Maria Méndez-Hernández⁷  Agustí Rodríguez-Palmero⁷  Victoria Fumadó⁸  Laura Planas-Serra⁸  Patricia Flores-Pérez⁸  Carlos Rodrigo⁹  Eduardo López-Granados^1,10  Roger Colobran^1,10  Pere Soler-Palacín^1,11  Jacques G. Rivière^1,12  Montserrat Ruiz^1,13 

[1] Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain;Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Barcelona, Spain;Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Catalonia, Spain;Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Barcelona, Spain;Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain;Navarra Health Service Hospital, Pamplona, Spain;Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain;Pediatric Critical Care Unit, Hospital Universitari Sant Joan de Deu, Barcelona, Catalonia, Spain;Pediatrics Department, Hospital Universitario Niño Jesús, Madrid, Spain;Servicio de Pediatría del Hospital Universitario Marqués de Valdecilla, Santander, Spain;Unitat de Malalties Infeccioses i Importades, Servei de Pediatría, Infectious and Imported Diseases, Pediatric Unit, Hospital Universitari Sant Joan de Deú, Barcelona, Catalonia, Spain;University Hospital of Burgos, Burgos, Spain;

关键词: Multisystem inflammatory syndrome in children;    COVID-19;    Kawasaki disease;    Epigenetics;    DNA methylation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: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-MIS-C = 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.

【 授权许可】

Unknown