Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy
BackgroundDuchenne 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 re...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2020.00605/full |
| _version_ | 1818329320576253952 |
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| author | Chiara Passarelli 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 Giuseppe Novelli Sonia Messina Marika Pane Eugenio Mercuri Mireille Claustres Sylvie Tuffery-Giraud Annemieke Aartsma-Rus Annemieke Aartsma-Rus Pietro Spitali Peter A. C. T’Hoen Peter A. C. T’Hoen Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Kristin Strandberg Cristina Al-Khalili Ekaterina Kotelnikova Michael Lebowitz Elena Schwartz Francesco Muntoni Francesco Muntoni Francesco Muntoni Chiara Scapoli Alessandra Ferlini Alessandra Ferlini |
| author_facet | Chiara Passarelli 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 Giuseppe Novelli Sonia Messina Marika Pane Eugenio Mercuri Mireille Claustres Sylvie Tuffery-Giraud Annemieke Aartsma-Rus Annemieke Aartsma-Rus Pietro Spitali Peter A. C. T’Hoen Peter A. C. T’Hoen Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Kristin Strandberg Cristina Al-Khalili Ekaterina Kotelnikova Michael Lebowitz Elena Schwartz Francesco Muntoni Francesco Muntoni Francesco Muntoni Chiara Scapoli Alessandra Ferlini Alessandra Ferlini |
| author_sort | Chiara Passarelli |
| collection | DOAJ |
| description | BackgroundDuchenne 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 FindingsWe 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.ConclusionWe have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker. |
| first_indexed | 2024-12-13T12:46:11Z |
| format | Article |
| id | doaj.art-b81fc57f071f44379d499b268e34d2eb |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-13T12:46:11Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-b81fc57f071f44379d499b268e34d2eb2022-12-21T23:45:29ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-07-011110.3389/fgene.2020.00605481974Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular DystrophyChiara Passarelli0Chiara Passarelli1Rita Selvatici2Alberto Carrieri3Francesca Romana Di Raimo4Maria Sofia Falzarano5Fernanda Fortunato6Rachele Rossi7Volker Straub8Katie Bushby9Mojgan Reza10Irina Zharaieva11Adele D’Amico12Enrico Bertini13Luciano Merlini14Patrizia Sabatelli15Paola Borgiani16Giuseppe Novelli17Giuseppe Novelli18Sonia Messina19Marika Pane20Eugenio Mercuri21Mireille Claustres22Sylvie Tuffery-Giraud23Annemieke Aartsma-Rus24Annemieke Aartsma-Rus25Pietro Spitali26Peter A. C. T’Hoen27Peter A. C. T’Hoen28Hanns Lochmüller29Hanns Lochmüller30Hanns Lochmüller31Hanns Lochmüller32Hanns Lochmüller33Kristin Strandberg34Cristina Al-Khalili35Ekaterina Kotelnikova36Michael Lebowitz37Elena Schwartz38Francesco Muntoni39Francesco Muntoni40Francesco Muntoni41Chiara Scapoli42Alessandra Ferlini43Alessandra Ferlini44Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyU.O.C. Laboratory of Medical Genetics, Paediatric Hospital Bambino Gesù, IRCCS, Rome, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyDepartment of Life Sciences and Biotechnology, University of Ferrara, Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United KingdomJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United KingdomJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United KingdomDubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United KingdomMolecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, Paediatric Hospital Bambino Gesù, IRCCS, Rome, ItalyMolecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, Paediatric Hospital Bambino Gesù, IRCCS, Rome, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyIRCCS Rizzoli & Institute of Molecular Genetics, National Research Council of Italy, Bologna, ItalyGenetics Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, ItalyGenetics Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy0Istituto Neuromed, IRCCS, Pozzilli, Italy1Department of Clinical and Experimental Medicine, Nemo Sud Clinical Center, University of Messina, Messina, Italy2Paediatric Neurology Unit, Centro Clinico Nemo, IRCCS Fondazione Policlinico A. Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy2Paediatric Neurology Unit, Centro Clinico Nemo, IRCCS Fondazione Policlinico A. Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy3Laboratory of Genetics of Rare Diseases, University of Montpellier, Montpellier, France3Laboratory of Genetics of Rare Diseases, University of Montpellier, Montpellier, FranceJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands5Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands6Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center – University of Freiburg, Freiburg, Germany7Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain8Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada9Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada0Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada1Department of Systems Biology, School of Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, Stockholm, Sweden1Department of Systems Biology, School of Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, Stockholm, Sweden2Panacea Pharmaceuticals, Gaithersburg, MD, United States2Panacea Pharmaceuticals, Gaithersburg, MD, United States3National Cancer Institute, Bethesda, MD, United StatesDubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom4NIH Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom5Great Ormond Street Hospital Trust, London, United KingdomDepartment of Life Sciences and Biotechnology, University of Ferrara, Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyDubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United KingdomBackgroundDuchenne 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 FindingsWe 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.ConclusionWe have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.https://www.frontiersin.org/article/10.3389/fgene.2020.00605/fullbiomarkercorticosteroid (betamethasone)receptorTNFRDuchenne |
| spellingShingle | Chiara Passarelli 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 Giuseppe Novelli Sonia Messina Marika Pane Eugenio Mercuri Mireille Claustres Sylvie Tuffery-Giraud Annemieke Aartsma-Rus Annemieke Aartsma-Rus Pietro Spitali Peter A. C. T’Hoen Peter A. C. T’Hoen Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Hanns Lochmüller Kristin Strandberg Cristina Al-Khalili Ekaterina Kotelnikova Michael Lebowitz Elena Schwartz Francesco Muntoni Francesco Muntoni Francesco Muntoni Chiara Scapoli Alessandra Ferlini Alessandra Ferlini Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy Frontiers in Genetics biomarker corticosteroid (betamethasone) receptor TNFR Duchenne |
| title | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| title_full | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| title_fullStr | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| title_full_unstemmed | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| title_short | Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy |
| title_sort | tumor necrosis factor receptor sf10a tnfrsf10a snps correlate with corticosteroid response in duchenne muscular dystrophy |
| topic | biomarker corticosteroid (betamethasone) receptor TNFR Duchenne |
| url | https://www.frontiersin.org/article/10.3389/fgene.2020.00605/full |
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