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Normal ATXN3 Allele but Not CHIP Polymorphisms Modulates Age at Onset in Machado-Joseph Disease.

França MC, Emmel VE, D'Abreu A, Maurer-Morelli CV, Secolin R, Bonadia LC, da Silva MS, Nucci A, Jardim LB, Saraiva-Pereira ML, Marques W, Paulson H, Lopes-Cendes I - Front Neurol (2012)

Bottom Line: 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.Indeed, we found that the normal CAG allele at ATXN3 had a positive independent effect on AO.The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Campinas Campinas, Brazil.

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.

Conclusion: The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.

No MeSH data available.


Related in: MedlinePlus

Distribution of normal ATXN3 (CAG) repeat alleles in the extremely early (black column) and late (dashed column) onset groups (A). Distribution of genotypes for the SNP rs6597 within the CHIP gene in the extremely early (black column) and late (dashed column) onset groups (B).
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Figure 2: Distribution of normal ATXN3 (CAG) repeat alleles in the extremely early (black column) and late (dashed column) onset groups (A). Distribution of genotypes for the SNP rs6597 within the CHIP gene in the extremely early (black column) and late (dashed column) onset groups (B).

Mentions: Statistical power analysis revealed that the power of our sample to detect a genetic association was 99.86%. According to residual AO corrected for expanded (CAG) repeats, there were 34 and 33 patients in the extremely early and late onset groups, respectively. The mean AO differed significantly between groups (26.4 ± 8.4 vs. 48.7 ± 6.3, Mann–Whitney p < 0.001), but there was no significant difference in the length of the (CAG) repeat expansion (72 ± 3.7 vs. 71 ± 3.0, Mann–Whitney p = 0.350). The distribution of normal ATXN3 (CAG) repeat alleles was also similar in the two groups (Mann–Whitney p = 0.217, Figure 2A). Allele and genotype frequencies for rs6597 did not differ between the two groups (Mann–Whitney p = 0.392 and 0.435, respectively; Figure 2B).


Normal ATXN3 Allele but Not CHIP Polymorphisms Modulates Age at Onset in Machado-Joseph Disease.

França MC, Emmel VE, D'Abreu A, Maurer-Morelli CV, Secolin R, Bonadia LC, da Silva MS, Nucci A, Jardim LB, Saraiva-Pereira ML, Marques W, Paulson H, Lopes-Cendes I - Front Neurol (2012)

Distribution of normal ATXN3 (CAG) repeat alleles in the extremely early (black column) and late (dashed column) onset groups (A). Distribution of genotypes for the SNP rs6597 within the CHIP gene in the extremely early (black column) and late (dashed column) onset groups (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3500826&req=5

Figure 2: Distribution of normal ATXN3 (CAG) repeat alleles in the extremely early (black column) and late (dashed column) onset groups (A). Distribution of genotypes for the SNP rs6597 within the CHIP gene in the extremely early (black column) and late (dashed column) onset groups (B).
Mentions: Statistical power analysis revealed that the power of our sample to detect a genetic association was 99.86%. According to residual AO corrected for expanded (CAG) repeats, there were 34 and 33 patients in the extremely early and late onset groups, respectively. The mean AO differed significantly between groups (26.4 ± 8.4 vs. 48.7 ± 6.3, Mann–Whitney p < 0.001), but there was no significant difference in the length of the (CAG) repeat expansion (72 ± 3.7 vs. 71 ± 3.0, Mann–Whitney p = 0.350). The distribution of normal ATXN3 (CAG) repeat alleles was also similar in the two groups (Mann–Whitney p = 0.217, Figure 2A). Allele and genotype frequencies for rs6597 did not differ between the two groups (Mann–Whitney p = 0.392 and 0.435, respectively; Figure 2B).

Bottom Line: 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.Indeed, we found that the normal CAG allele at ATXN3 had a positive independent effect on AO.The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Campinas Campinas, Brazil.

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.

Conclusion: The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.

No MeSH data available.


Related in: MedlinePlus