Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs correlate with corticosteroid response in duchenne muscular dystrophy

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• dc.contributor.author Passarelli, Chiara
• dc.contributor.author Lochmüller, Hanns
• dc.contributor.author Ferlini, Alessandra
• dc.date.accessioned 2020-10-20T06:01:00Z
• dc.date.available 2020-10-20T06:01:00Z
• dc.date.issued 2020
• dc.description.abstract Background: Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment. Methods and findings: We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in the TNFRSF10A gene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N = 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results. Conclusion: We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.
• dc.description.sponsorship The EU BIO-NMD project no. 241665 and the SOLVE-RD project (H2020 ID: 779257) were supported this study. FM was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The support of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre and of the MRC Neuromuscular Centre and BRC Biobank is also gratefully acknowledged. Part of this study was also supported by the NIHR grant “Rare Diseases Translational Research Collaboration” on Duchenne muscular dystrophy to FM. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). The EUROBIOBANK, European Network of DNA, Cell and Tissue Banks for Rare Diseases was also acknowledged.
• dc.format.mimetype application/pdf
• dc.identifier.citation Passarelli C, Selvatici R, Carrieri A, Di Raimo FR, Falzarano MS, Fortunato F et al. Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs correlate with corticosteroid response in duchenne muscular dystrophy. Front Genet. 2020; 11:605. DOI: 10.3389/fgene.2020.00605
• dc.identifier.doi http://dx.doi.org/10.3389/fgene.2020.00605
• dc.identifier.issn 1664-8021
• dc.identifier.uri http://hdl.handle.net/10230/45515
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Genet. 2020; 11:605
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/241665
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
• dc.rights © 2020 Passarelli, Selvatici, Carrieri, Di Raimo, Falzarano, Fortunato, Rossi, Straub, Bushby, Reza, Zharaieva, D’Amico, Bertini, Merlini, Sabatelli, Borgiani, Novelli, Messina, Pane, Mercuri, Claustres, Tuffery-Giraud, Aartsma-Rus, Spitali, T’Hoen, Lochmüller, Strandberg, Al-Khalili, Kotelnikova, Lebowitz, Schwartz, Muntoni, Scapoli and Ferlini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Duchenne
• dc.subject.keyword TNFR
• dc.subject.keyword Biomarker
• dc.subject.keyword Corticosteroid (betamethasone)
• dc.subject.keyword Receptor
• dc.title Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs correlate with corticosteroid response in duchenne muscular dystrophy
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion