Validation of genetic modifiers for Duchenne muscular dystrophy: A multicentre study assessing SPP1 and LTBP4 variants

Janneke C. Van Den Bergen, Monika Hiller, Stefan Böhringer, Linda Vijfhuizen, Hendrika B. Ginjaar, Amina Chaouch, Kate Bushby, Volker Straub, Mariacristina Scoto, Sebahattin Cirak, Véronique Humbertclaude, Mireille Claustres, Chiara Scotton, Chiara Passarelli, Hanns Lochmüller, Francesco Muntoni, Sylvie Tuffery-Giraud, Alessandra Ferlini, Annemieke M. Aartsma-Rus, Jan J G M VerschuurenPeter A C 'T Hoen, Pietro Spitali

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1060-1065
Number of pages6
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume86
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

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Duchenne Muscular Dystrophy
Multicenter Studies
Single Nucleotide Polymorphism
Genotype
Rare Diseases
Haplotypes
Walking
Steroids
Clinical Trials
Genes
Wheelchairs
Muscle Weakness
Genetic Association Studies
Freezing
Mass Spectrometry
Adrenal Cortex Hormones
Multivariate Analysis
Biomarkers
Modifier
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Surgery
  • Arts and Humanities (miscellaneous)

Cite this

Van Den Bergen, J. C., Hiller, M., Böhringer, S., Vijfhuizen, L., Ginjaar, H. B., Chaouch, A., ... Spitali, P. (2015). Validation of genetic modifiers for Duchenne muscular dystrophy: A multicentre study assessing SPP1 and LTBP4 variants. Journal of Neurology, Neurosurgery and Psychiatry, 86(10), 1060-1065. https://doi.org/10.1136/jnnp-2014-308409

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 A C; Spitali, Pietro.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 86, No. 10, 01.10.2015, p. 1060-1065.

Research output: Contribution to journalArticle

Van Den Bergen, JC, Hiller, M, Böhringer, S, Vijfhuizen, L, Ginjaar, HB, Chaouch, A, Bushby, K, Straub, V, Scoto, M, Cirak, S, Humbertclaude, V, Claustres, M, Scotton, C, Passarelli, C, Lochmüller, H, Muntoni, F, Tuffery-Giraud, S, Ferlini, A, Aartsma-Rus, AM, Verschuuren, JJGM, 'T Hoen, PAC & Spitali, P 2015, 'Validation of genetic modifiers for Duchenne muscular dystrophy: A multicentre study assessing SPP1 and LTBP4 variants', Journal of Neurology, Neurosurgery and Psychiatry, vol. 86, no. 10, pp. 1060-1065. https://doi.org/10.1136/jnnp-2014-308409
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 A C ; Spitali, Pietro. / Validation of genetic modifiers for Duchenne muscular dystrophy : A multicentre study assessing SPP1 and LTBP4 variants. In: Journal of Neurology, Neurosurgery and Psychiatry. 2015 ; Vol. 86, No. 10. pp. 1060-1065.
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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.",
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T1 - Validation of genetic modifiers for Duchenne muscular dystrophy

T2 - A multicentre study assessing SPP1 and LTBP4 variants

AU - Van Den Bergen, Janneke C.

AU - Hiller, Monika

AU - Böhringer, Stefan

AU - Vijfhuizen, Linda

AU - Ginjaar, Hendrika B.

AU - Chaouch, Amina

AU - Bushby, Kate

AU - Straub, Volker

AU - Scoto, Mariacristina

AU - Cirak, Sebahattin

AU - Humbertclaude, Véronique

AU - Claustres, Mireille

AU - Scotton, Chiara

AU - Passarelli, Chiara

AU - Lochmüller, Hanns

AU - Muntoni, Francesco

AU - Tuffery-Giraud, Sylvie

AU - Ferlini, Alessandra

AU - Aartsma-Rus, Annemieke M.

AU - Verschuuren, Jan J G M

AU - 'T Hoen, Peter A C

AU - Spitali, Pietro

PY - 2015/10/1

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N2 - 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.

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