TY - JOUR
T1 - SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy
AU - Pegoraro, E.
AU - Hoffman, E. P.
AU - Piva, L.
AU - Gavassini, B. F.
AU - Cagnin, S.
AU - Ermani, M.
AU - Bello, L.
AU - Soraru, G.
AU - Pacchioni, B.
AU - Bonifati, M. D.
AU - Lanfranchi, G.
AU - Angelini, C.
AU - Kesari, A.
AU - Lee, I.
AU - Gordish-Dressman, H.
AU - Devaney, J. M.
AU - McDonald, C. M.
PY - 2011/1/18
Y1 - 2011/1/18
N2 - 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.
AB - 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.
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U2 - 10.1212/WNL.0b013e318207afeb
DO - 10.1212/WNL.0b013e318207afeb
M3 - Article
C2 - 21178099
AN - SCOPUS:78751634526
VL - 76
SP - 219
EP - 226
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 3
ER -