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Localization of sequence variations in PGC-1alpha influence their modifying effect in Huntington disease.

Authors: Che, HV  Metzger, S  Portal, E  Deyle, C  Riess, O  Nguyen, HP 
Citation: Che HV, etal., Mol Neurodegener. 2011 Jan 6;6(1):1. doi: 10.1186/1750-1326-6-1.
Pubmed: (View Article at PubMed) PMID:21211002
DOI: Full-text: DOI:10.1186/1750-1326-6-1

BACKGROUND: Huntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1alpha (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1alpha is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD. RESULTS: Two SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset. CONCLUSION: Therefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1alpha dysfunction is involved in HD pathology.

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RGD Object Information
RGD ID: 10395290
Created: 2015-08-28
Species: All species
Last Modified: 2015-08-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.