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The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

Weydt P, Soyal SM, Gellera C, Didonato S, Weidinger C, Oberkofler H, Landwehrmeyer GB, Patsch W - Mol Neurodegener (2009)

Bottom Line: We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles.Block 1 haplotypes were not associated with the age-at-onset.Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Ulm (P,W,; G,B,L,), Ulm, Germany. patrick.weydt@uni-ulm.de.

ABSTRACT
Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction and enhanced oxidative stress have been implicated in the pathogenesis. Recent studies suggest that PGC-1alpha, a transcriptional master regulator of mitochondrial biogenesis and metabolism, is defective in HD. A genome wide search for modifier genes of HD age-of-onset had suggested linkage at chromosomal region 4p16-4p15, near the locus of PPARGC1A, the gene coding for PGC-1alpha. We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles. Block 1 haplotypes were not associated with the age-at-onset. Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset. To our knowledge this is the first study to show clinically relevant effects of the PGC-1alpha system on the course of Huntington's disease in humans.

No MeSH data available.


Related in: MedlinePlus

Polymorphisms and haplotype blocks in PPARGC1A. Linear map with exons (full boxes), SNP positions are relative to the translational start site. MAF indicates minor allele frequency; typing studies in other populations showed that, unlike in the HD population studied, C > T at rs6821591; SNP qualifiers refer to database entries . SNPs not used in the initial haplotyping studies are shown above the linear map. The extension of haplotype blocks is shown at the bottom. Scales differ for the transcribed sequence and the 5'-untranscribed sequence.
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Figure 1: Polymorphisms and haplotype blocks in PPARGC1A. Linear map with exons (full boxes), SNP positions are relative to the translational start site. MAF indicates minor allele frequency; typing studies in other populations showed that, unlike in the HD population studied, C > T at rs6821591; SNP qualifiers refer to database entries . SNPs not used in the initial haplotyping studies are shown above the linear map. The extension of haplotype blocks is shown at the bottom. Scales differ for the transcribed sequence and the 5'-untranscribed sequence.

Mentions: Distributions of genotypes at all SNPs did not deviate significantly from Hardy-Weinberg expectations. As expected, the pairwise LD matrix revealed two main haplotype blocks, previously identified in other populations[21]. In each haplotype block, 5 common haplotypes with frequencies > 0.01 were inferred that accounted for > 97% of the chromosomes. For each of the common haplotypes, the squared correlation between true and predicted haplotype dose was > 0.97 (Fig. 1). No associations were observed between block 1 haplotypes and age-at-onset (data not shown). Rs6821591, located in haploblock 2 in the 3-untranslated region, displayed an association in the dominant model (P = 0.0178). Furthermore, global testing suggested an association between block 2 haplotypes and age at onset (Table 1). In particular, haplotype-specific statistics scores were highest and lowest for haplotypes 0001 and 0000, respectively. The estimated difference in age at onset between these two haplotypes was 2.8 years. Consequently, rs6821591, discriminating haplotypes 0001 and 0000, was found to be associated with the age at onset after adjustment for linkage disequilibrium between the SNPs forming haploblock 2 (P = 0.0025).


The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

Weydt P, Soyal SM, Gellera C, Didonato S, Weidinger C, Oberkofler H, Landwehrmeyer GB, Patsch W - Mol Neurodegener (2009)

Polymorphisms and haplotype blocks in PPARGC1A. Linear map with exons (full boxes), SNP positions are relative to the translational start site. MAF indicates minor allele frequency; typing studies in other populations showed that, unlike in the HD population studied, C > T at rs6821591; SNP qualifiers refer to database entries . SNPs not used in the initial haplotyping studies are shown above the linear map. The extension of haplotype blocks is shown at the bottom. Scales differ for the transcribed sequence and the 5'-untranscribed sequence.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2630305&req=5

Figure 1: Polymorphisms and haplotype blocks in PPARGC1A. Linear map with exons (full boxes), SNP positions are relative to the translational start site. MAF indicates minor allele frequency; typing studies in other populations showed that, unlike in the HD population studied, C > T at rs6821591; SNP qualifiers refer to database entries . SNPs not used in the initial haplotyping studies are shown above the linear map. The extension of haplotype blocks is shown at the bottom. Scales differ for the transcribed sequence and the 5'-untranscribed sequence.
Mentions: Distributions of genotypes at all SNPs did not deviate significantly from Hardy-Weinberg expectations. As expected, the pairwise LD matrix revealed two main haplotype blocks, previously identified in other populations[21]. In each haplotype block, 5 common haplotypes with frequencies > 0.01 were inferred that accounted for > 97% of the chromosomes. For each of the common haplotypes, the squared correlation between true and predicted haplotype dose was > 0.97 (Fig. 1). No associations were observed between block 1 haplotypes and age-at-onset (data not shown). Rs6821591, located in haploblock 2 in the 3-untranslated region, displayed an association in the dominant model (P = 0.0178). Furthermore, global testing suggested an association between block 2 haplotypes and age at onset (Table 1). In particular, haplotype-specific statistics scores were highest and lowest for haplotypes 0001 and 0000, respectively. The estimated difference in age at onset between these two haplotypes was 2.8 years. Consequently, rs6821591, discriminating haplotypes 0001 and 0000, was found to be associated with the age at onset after adjustment for linkage disequilibrium between the SNPs forming haploblock 2 (P = 0.0025).

Bottom Line: We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles.Block 1 haplotypes were not associated with the age-at-onset.Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Ulm (P,W,; G,B,L,), Ulm, Germany. patrick.weydt@uni-ulm.de.

ABSTRACT
Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction and enhanced oxidative stress have been implicated in the pathogenesis. Recent studies suggest that PGC-1alpha, a transcriptional master regulator of mitochondrial biogenesis and metabolism, is defective in HD. A genome wide search for modifier genes of HD age-of-onset had suggested linkage at chromosomal region 4p16-4p15, near the locus of PPARGC1A, the gene coding for PGC-1alpha. We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles. Block 1 haplotypes were not associated with the age-at-onset. Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset. To our knowledge this is the first study to show clinically relevant effects of the PGC-1alpha system on the course of Huntington's disease in humans.

No MeSH data available.


Related in: MedlinePlus