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Neuromuscular
Research paper
Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants
  1. Janneke C van den Bergen1,
  2. Monika Hiller2,
  3. Stefan Böhringer3,
  4. Linda Vijfhuizen4,
  5. Hendrika B Ginjaar4,
  6. Amina Chaouch5,
  7. Kate Bushby5,
  8. Volker Straub5,
  9. Mariacristina Scoto6,
  10. Sebahattin Cirak6,7,
  11. Véronique Humbertclaude8,
  12. Mireille Claustres8,
  13. Chiara Scotton9,
  14. Chiara Passarelli10,
  15. Hanns Lochmüller5,
  16. Francesco Muntoni6,
  17. Sylvie Tuffery-Giraud8,
  18. Alessandra Ferlini9,
  19. Annemieke M Aartsma-Rus2,
  20. Jan J G M Verschuuren1,
  21. Peter AC 't Hoen2,
  22. Pietro Spitali2
  1. 1Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
  6. 6Dubowitz Neuromuscular Centre, University College London, London, UK
  7. 7Children's National Medical Center, Research Center for Genetic Medicine, Washington DC, USA
  8. 8Laboratoire de Génétique de Maladies Rares, CHU Montpellier, Université Montpellier 1, UFR Médecine, and Inserm U827, Montpellier, France
  9. 9Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
  10. 10Paediatric Hospital Bambino Gesù, Rome, Italy
  1. Correspondence to Dr Pietro Spitali, Department of Human Genetics, Leiden University Medical Center (LUMC), PO Box 9600, Leiden 2300 RC, The Netherlands; p.spitali{at}lumc.nl

Abstract

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.

  • MUSCULAR DYSTROPHY
  • MUSCLE DISEASE
  • GENETICS
  • DYSTROPHIN
  • NEUROMUSCULAR

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/

https://doi.org/10.1136/jnnp-2014-308409

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