SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy

E. Pegoraro, E. P. Hoffman, L. Piva, B. F. Gavassini, S. Cagnin, M. Ermani, L. Bello, G. Soraru, B. Pacchioni, M. D. Bonifati, G. Lanfranchi, C. Angelini, A. Kesari, I. Lee, H. Gordish-Dressman, J. M. Devaney, Craig M McDonald

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)219-226
Number of pages8
JournalNeurology
Volume76
Issue number3
DOIs
StatePublished - Jan 18 2011

Fingerprint

Duchenne Muscular Dystrophy
Genotype
Osteopontin
Glucocorticoids
Disease Progression
Lethal Genes
Inborn Genetic Diseases
Genome-Wide Association Study
Hand Strength
Natural History
Research
Single Nucleotide Polymorphism
Healthy Volunteers
Alleles
Clinical Trials
Phenotype
Muscles
Messenger RNA
Genes

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pegoraro, E., Hoffman, E. P., Piva, L., Gavassini, B. F., Cagnin, S., Ermani, M., ... McDonald, C. M. (2011). SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology, 76(3), 219-226. https://doi.org/10.1212/WNL.0b013e318207afeb

SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. / Pegoraro, E.; Hoffman, E. P.; Piva, L.; Gavassini, B. F.; Cagnin, S.; Ermani, M.; Bello, L.; Soraru, G.; Pacchioni, B.; Bonifati, M. D.; Lanfranchi, G.; Angelini, C.; Kesari, A.; Lee, I.; Gordish-Dressman, H.; Devaney, J. M.; McDonald, Craig M.

In: Neurology, Vol. 76, No. 3, 18.01.2011, p. 219-226.

Research output: Contribution to journalArticle

Pegoraro, E, Hoffman, EP, Piva, L, Gavassini, BF, Cagnin, S, Ermani, M, Bello, L, Soraru, G, Pacchioni, B, Bonifati, MD, Lanfranchi, G, Angelini, C, Kesari, A, Lee, I, Gordish-Dressman, H, Devaney, JM & McDonald, CM 2011, 'SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy', Neurology, vol. 76, no. 3, pp. 219-226. https://doi.org/10.1212/WNL.0b013e318207afeb
Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani M et al. SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology. 2011 Jan 18;76(3):219-226. https://doi.org/10.1212/WNL.0b013e318207afeb
Pegoraro, E. ; Hoffman, E. P. ; Piva, L. ; Gavassini, B. F. ; Cagnin, S. ; Ermani, M. ; Bello, L. ; Soraru, G. ; Pacchioni, B. ; Bonifati, M. D. ; Lanfranchi, G. ; Angelini, C. ; Kesari, A. ; Lee, I. ; Gordish-Dressman, H. ; Devaney, J. M. ; McDonald, Craig M. / SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. In: Neurology. 2011 ; Vol. 76, No. 3. pp. 219-226.
@article{254274823dca43d08d8c3ded40eec633,
title = "SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy",
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.",
author = "E. Pegoraro and Hoffman, {E. P.} and L. Piva and Gavassini, {B. F.} and S. Cagnin and M. Ermani and L. Bello and G. Soraru and B. Pacchioni and Bonifati, {M. D.} and G. Lanfranchi and C. Angelini and A. Kesari and I. Lee and H. Gordish-Dressman and Devaney, {J. M.} and McDonald, {Craig M}",
year = "2011",
month = "1",
day = "18",
doi = "10.1212/WNL.0b013e318207afeb",
language = "English (US)",
volume = "76",
pages = "219--226",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

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, Craig 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.

UR - http://www.scopus.com/inward/record.url?scp=78751634526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78751634526&partnerID=8YFLogxK

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 -