title: Normal ATXN3 Allele but Not CHIP Polymorphisms Modulates Age at Onset in Machado-Joseph Disease.
abstract: BACKGROUND
  Age at onset (AO) in Machado-Joseph disease (MJD) is closely associated with the length of the CAG repeat at the mutant ATXN3 allele, but there are other intervening factors. Experimental evidence indicates that the normal ATXN3 allele and the C-terminal heat shock protein 70 (Hsp70)-interacting protein (CHIP) may be genetic modifiers of AO in MJD.
  
  
  METHODS
  To investigate this hypothesis, we determined the length of normal and expanded CAG repeats at the ATXN3 gene in 210 unrelated patients with MJD. In addition, we genotyped five single nucleotide polymorphisms (SNPs) within the CHIP gene. We first compared the frequencies of the different genotypes in two subgroups of patients who were highly discordant for AO after correction for the length of the expanded CAG allele. The possible modifier effect of each gene was then evaluated in a stepwise multiple linear regression model.
  
  
  RESULTS
  AO was associated with the length of the expanded CAG allele (r(2) = 0.596, p < 0.001). Frequencies of the normal CAG repeats at the ATXN3 gene and of CHIP polymorphisms did not differ significantly between groups with highly discordant ages at onset. However, addition of the normal allele improved the model fit for prediction of AO (r(2) = 0.604, p = 0.014). Indeed, we found that the normal CAG allele at ATXN3 had a positive independent effect on AO.
  
  
  CONCLUSIONS
  The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.
authors.affiliation: Department of Neurology, University of Campinas Campinas, Brazil.
authors.forename: Marcondes C
authors.initials: MC
authors.lastname: França
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Emmel
authors.forename: Anelyssa
authors.initials: A
authors.lastname: D'Abreu
authors.forename: Cláudia V
authors.initials: CV
authors.lastname: Maurer-Morelli
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Secolin
authors.forename: Luciana Cardoso
authors.initials: LC
authors.lastname: Bonadia
authors.forename: Marilza Santos
authors.initials: MS
authors.lastname: da Silva
authors.forename: Anamarli
authors.initials: A
authors.lastname: Nucci
authors.forename: Laura Bannach
authors.initials: LB
authors.lastname: Jardim
authors.forename: Maria Luiza
authors.initials: ML
authors.lastname: Saraiva-Pereira
authors.forename: Wilson
authors.initials: W
authors.lastname: Marques
authors.forename: Henry
authors.initials: H
authors.lastname: Paulson
authors.forename: Iscia
authors.initials: I
authors.lastname: Lopes-Cendes