Table_1_Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy.docx (35.5 kB)
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Table_1_Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy.docx

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posted on 2020-07-03, 14:37 authored by Chiara Passarelli, Rita Selvatici, Alberto Carrieri, Francesca Romana Di Raimo, Maria Sofia Falzarano, Fernanda Fortunato, Rachele Rossi, Volker Straub, Katie Bushby, Mojgan Reza, Irina Zharaieva, Adele D’Amico, Enrico Bertini, Luciano Merlini, Patrizia Sabatelli, Paola Borgiani, Giuseppe Novelli, Sonia Messina, Marika Pane, Eugenio Mercuri, Mireille Claustres, Sylvie Tuffery-Giraud, Annemieke Aartsma-Rus, Pietro Spitali, Peter A. C. T’Hoen, Hanns Lochmüller, Kristin Strandberg, Cristina Al-Khalili, Ekaterina Kotelnikova, Michael Lebowitz, Elena Schwartz, Francesco Muntoni, Chiara Scapoli, Alessandra Ferlini

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.


We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.