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.
authors.affiliation: Neuromuscular Center, Department of Neurosciences, University of Padova, 35128 Padova, Italy elena.pegoraro@unipd.it.
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: L
authors.initials: L
authors.lastname: Piva
authors.forename: B F
authors.initials: BF
authors.lastname: Gavassini
authors.forename: S
authors.initials: S
authors.lastname: Cagnin
authors.forename: M
authors.initials: M
authors.lastname: Ermani
authors.forename: L
authors.initials: L
authors.lastname: Bello
authors.forename: G
authors.initials: G
authors.lastname: Soraru
authors.forename: B
authors.initials: B
authors.lastname: Pacchioni
authors.forename: M D
authors.initials: MD
authors.lastname: Bonifati
authors.forename: G
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: A
authors.initials: A
authors.lastname: Kesari
authors.forename: I
authors.initials: I
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: J M
authors.initials: JM
authors.lastname: Devaney
authors.forename: C M
authors.initials: CM
authors.lastname: McDonald
mesh_terms: D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007391:International Cooperation; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016017:Odds Ratio; D053495:Osteopontin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D005938:Glucocorticoids; C506895:SPP1 protein, human; D053495:Osteopontin