van den Bergen, JC; Hiller, M; Böhringer, S; Vijfhuizen, L; Ginjaar, I; Chaouch, A; Bushby, K; ... Spitali, P; + view all van den Bergen, JC; Hiller, M; Böhringer, S; Vijfhuizen, L; Ginjaar, I; Chaouch, A; Bushby, K; Straub, V; Scoto, M; Cirak, S; Claustres, M; Scotton, C; Passarelli, C; Lochmüller, H; Muntoni, F; Tuffery-Giraud, S; Ferlini, A; Aartsma-Rus, A; Verschuuren, J; 't Hoen, PAC; Spitali, P; - view fewer (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. 10.1136/jnnp-2014-308409.

Text J_Neurol_Neurosurg_Psychiatry-2014-van_den_Bergen-jnnp-2014-308409.pdf Download (1MB)

Abstract

OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness. It has been recently 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 DMD patients. 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.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item