Passarelli, C;
Selvatici, R;
Carrieri, A;
Di Raimo, FR;
Falzarano, MS;
Fortunato, F;
Rossi, R;
... Ferlini, A; + view all
(2020)
Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy.
Frontiers in Genetics
, 11
, Article 605. 10.3389/fgene.2020.00605.
Preview |
Text
Muntoni_Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy_VoR.pdf - Published Version Download (2MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fgene.2020.00605 |
| Publisher version: | http://dx.doi.org/10.3389/fgene.2020.00605 |
| Language: | English |
| Additional information: | © 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. |
| Keywords: | Duchenne, TNFR, biomarker, corticosteroid (betamethasone), receptor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107497 |
Archive Staff Only
 |
View Item |
