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.