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Abstract
Objective: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient–patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers.
Methods: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Results: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%–19% less grip strength (CINRG cohort p = 0.0003).
Conclusions: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
Footnotes
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Study funding: Supported by grants from NIH 1U54HD053177 (Wellstone Muscular Dystrophy Center), National Center for Medical Rehabilitation Research (5R24HD050846), Department of Defense (03108001), National Institute on Disability and Rehabilitation Research (H133B031118), Intellectual and Developmental Disabilities Research Center (1U54HD053177), and the Italian PRIN (n. 2004058593_002). Also supported by the Eurobiobank network (QLRT2001-027769 to C.A.) and Telethon Bank (GTF05003).
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The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Editorial, page 208
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Supplemental data at www.neurology.org
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- CI
- confidence interval
- CINRG
- Cooperative International Neuromuscular Research Group
- COA
- correspondence analysis
- DMD
- Duchenne muscular dystrophy
- GWAS
- genome-wide association studies
- MRC
- Medical Research Council
- SNP
- single nucleotide polymorphism
- ST
- supported tree hierarchical clustering
- Received January 26, 2010.
- Accepted July 27, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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