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

Neurology. 2011 Jan 18;76(3):219-26. doi: 10.1212/WNL.0b013e318207afeb. Epub 2010 Dec 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Disease Progression
  • Female
  • Genotype
  • Glucocorticoids / administration & dosage
  • Humans
  • International Cooperation
  • Italy
  • Kaplan-Meier Estimate
  • Male
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / physiopathology
  • Odds Ratio
  • Osteopontin / genetics*
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Reverse Transcriptase Polymerase Chain Reaction
  • Severity of Illness Index

Substances

  • Glucocorticoids
  • SPP1 protein, human
  • Osteopontin