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PGC-1alpha as modifier of onset age in Huntington disease.

ABSTRACT: Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.

SUBMITTER: Taherzadeh-Fard E

PROVIDER: S-EPMC2644307 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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PGC-1alpha as modifier of onset age in Huntington disease.

Taherzadeh-Fard Elahe E Saft Carsten C Andrich Jürgen J Wieczorek Stefan S Arning Larissa L

Molecular neurodegeneration 20090206

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link bet ...[more]

PMID: 19200361

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Project description:Peroxisome proliferator-activated receptor-? co-activator (PGC)-1? is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1?. We hypothesized that the rs8192678 PGC-1? single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1? SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.The rs8192678 PGC-1? SNP was not associated with the risk of PD. However, an association of the PGC-1? rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027).These data reveal possible associations of the PGC-1? SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1? rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1? in PD and longevity.

Dataset Information

PGC-1alpha as modifier of onset age in Huntington disease.

Publications

PGC-1alpha as modifier of onset age in Huntington disease.

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