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Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants
OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602257/ https://www.ncbi.nlm.nih.gov/pubmed/25476005 http://dx.doi.org/10.1136/jnnp-2014-308409 |
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author | van den Bergen, Janneke C Hiller, Monika Böhringer, Stefan Vijfhuizen, Linda Ginjaar, Hendrika B Chaouch, Amina Bushby, Kate Straub, Volker Scoto, Mariacristina Cirak, Sebahattin Humbertclaude, Véronique Claustres, Mireille Scotton, Chiara Passarelli, Chiara Lochmüller, Hanns Muntoni, Francesco Tuffery-Giraud, Sylvie Ferlini, Alessandra Aartsma-Rus, Annemieke M Verschuuren, Jan J G M 't Hoen, Peter AC Spitali, Pietro |
author_facet | van den Bergen, Janneke C Hiller, Monika Böhringer, Stefan Vijfhuizen, Linda Ginjaar, Hendrika B Chaouch, Amina Bushby, Kate Straub, Volker Scoto, Mariacristina Cirak, Sebahattin Humbertclaude, Véronique Claustres, Mireille Scotton, Chiara Passarelli, Chiara Lochmüller, Hanns Muntoni, Francesco Tuffery-Giraud, Sylvie Ferlini, Alessandra Aartsma-Rus, Annemieke M Verschuuren, Jan J G M 't Hoen, Peter AC Spitali, Pietro |
author_sort | van den Bergen, Janneke C |
collection | PubMed |
description | OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials. METHODS: Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates. RESULTS: We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss. CONCLUSIONS: This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials. |
format | Online Article Text |
id | pubmed-4602257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46022572015-10-21 Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants van den Bergen, Janneke C Hiller, Monika Böhringer, Stefan Vijfhuizen, Linda Ginjaar, Hendrika B Chaouch, Amina Bushby, Kate Straub, Volker Scoto, Mariacristina Cirak, Sebahattin Humbertclaude, Véronique Claustres, Mireille Scotton, Chiara Passarelli, Chiara Lochmüller, Hanns Muntoni, Francesco Tuffery-Giraud, Sylvie Ferlini, Alessandra Aartsma-Rus, Annemieke M Verschuuren, Jan J G M 't Hoen, Peter AC Spitali, Pietro J Neurol Neurosurg Psychiatry Neuromuscular OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials. METHODS: Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates. RESULTS: We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss. CONCLUSIONS: This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials. BMJ Publishing Group 2015-10 2014-12-04 /pmc/articles/PMC4602257/ /pubmed/25476005 http://dx.doi.org/10.1136/jnnp-2014-308409 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Neuromuscular van den Bergen, Janneke C Hiller, Monika Böhringer, Stefan Vijfhuizen, Linda Ginjaar, Hendrika B Chaouch, Amina Bushby, Kate Straub, Volker Scoto, Mariacristina Cirak, Sebahattin Humbertclaude, Véronique Claustres, Mireille Scotton, Chiara Passarelli, Chiara Lochmüller, Hanns Muntoni, Francesco Tuffery-Giraud, Sylvie Ferlini, Alessandra Aartsma-Rus, Annemieke M Verschuuren, Jan J G M 't Hoen, Peter AC Spitali, Pietro Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title | Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title_full | Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title_fullStr | Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title_full_unstemmed | Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title_short | Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants |
title_sort | validation of genetic modifiers for duchenne muscular dystrophy: a multicentre study assessing spp1 and ltbp4 variants |
topic | Neuromuscular |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602257/ https://www.ncbi.nlm.nih.gov/pubmed/25476005 http://dx.doi.org/10.1136/jnnp-2014-308409 |
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