SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy
E Pegoraro, EP Hoffman, L Piva, BF Gavassini… - Neurology, 2011 - AAN Enterprises
Neurology, 2011•AAN Enterprises
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) …
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) …
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.
American Academy of Neurology