Journal
NEUROLOGY
Volume 76, Issue 3, Pages 219-226Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e318207afeb
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Funding
- MEDA Pharmaceuticals Inc.
- Wellstone Grant [8568-01-01]
- Italian Telethon
- NIH (NICHD)
- PTC Therapeutics, Inc.
- Muscular Dystrophy Association
- Clinical Research Network in Duchenne Muscular Dystrophy
- NIH [1U54HD053177]
- 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]
- Italian PRIN [2004058593_002]
- Eurobiobank network [QLRT2001-027769]
- Telethon Bank [GTF05003]
- NIH (NINDS)
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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. Neurology (R) 2011; 76:219-226
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