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PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L - Mol Neurodegener (2011)

Bottom Line: In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD.When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany. larissa.arning@rub.de.

ABSTRACT

Background: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

Results: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

Conclusions: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

No MeSH data available.


Related in: MedlinePlus

Graphical representation of single-nucleotide polymorphisms (SNPs) in relation to the exon-intron structure (top) and the Haploview pairwise linkage disequilibrium (LD) structure of part of NRF-1 (bottom). Exons are indicated by solid black boxes, and the numbered vertical lines indicate positions of the SNPs analysed in NRF-1. Haploview plot showing pairwise LD (D' values) for all 15 SNPs based on genotypes of 401 HD patients of the study. Each square plots the level of LD between a pair of SNPs, comparisons between neighboring SNPs are arranged along the first line under the names of the SNPs. Dark grey coloring indicates strong LD, medium grey shading indicates less strong LD, light grey indicates intermediate LD, and white indicates weak LD. LD blocks are framed in black and were classified according to Gabriel et al. (2002).
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Figure 1: Graphical representation of single-nucleotide polymorphisms (SNPs) in relation to the exon-intron structure (top) and the Haploview pairwise linkage disequilibrium (LD) structure of part of NRF-1 (bottom). Exons are indicated by solid black boxes, and the numbered vertical lines indicate positions of the SNPs analysed in NRF-1. Haploview plot showing pairwise LD (D' values) for all 15 SNPs based on genotypes of 401 HD patients of the study. Each square plots the level of LD between a pair of SNPs, comparisons between neighboring SNPs are arranged along the first line under the names of the SNPs. Dark grey coloring indicates strong LD, medium grey shading indicates less strong LD, light grey indicates intermediate LD, and white indicates weak LD. LD blocks are framed in black and were classified according to Gabriel et al. (2002).

Mentions: In our cohort of 401 HD patients, the expanded HTT allele accounts for nearly 73% of the variance in motor AO (R2 = 0.729) and shows a highly significant influence on the AO (p < 0.0001). Multiple regression models were used to test all SNPs for association with the AO. Of these, four showed a nominal p-value < 0.05 (Table 2). For NRF-1, addition of the intronic variations rs7781972 and rs6949152 showed an association with the motor AO. Inclusion of the rs7781972 genotypes in the model increased the R2 statistic from 0.729 to 0.733 in both the dominant and the additive model (p = 0.017 and p = 0.011, Table 2). Inclusion of the rs6949152 genotypes increased the R2 from 0.729 to 0.734 (p = 0.004) according to the dominant model and to 0.733 (p = 0.013) in the additive model (Table 2). Examining linkage disequilibrium (LD) among the 15 NRF-1 variations revealed, that the variations rs10275661, rs10225103, rs7781972, rs10268267, rs6962005 and rs6949152 in IVS1 were in high LD in the cohort (D' = 1.0, r2 = 0.87-0.92). In 3' direction the LD breaks down, and a second block of very strong LD (D' = 1.0, r2 ≥ 0.98) is observed for rs10231985, rs11487138 and rs11761434. The remaining SNPs covering exon 2 to IVS10 (rs1882094, rs3735006, rs1962039, rs2402970, rs6948697 and rs10500120) showed lower LD coefficients (D') and r2 values (Figure 1).


PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L - Mol Neurodegener (2011)

Graphical representation of single-nucleotide polymorphisms (SNPs) in relation to the exon-intron structure (top) and the Haploview pairwise linkage disequilibrium (LD) structure of part of NRF-1 (bottom). Exons are indicated by solid black boxes, and the numbered vertical lines indicate positions of the SNPs analysed in NRF-1. Haploview plot showing pairwise LD (D' values) for all 15 SNPs based on genotypes of 401 HD patients of the study. Each square plots the level of LD between a pair of SNPs, comparisons between neighboring SNPs are arranged along the first line under the names of the SNPs. Dark grey coloring indicates strong LD, medium grey shading indicates less strong LD, light grey indicates intermediate LD, and white indicates weak LD. LD blocks are framed in black and were classified according to Gabriel et al. (2002).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117738&req=5

Figure 1: Graphical representation of single-nucleotide polymorphisms (SNPs) in relation to the exon-intron structure (top) and the Haploview pairwise linkage disequilibrium (LD) structure of part of NRF-1 (bottom). Exons are indicated by solid black boxes, and the numbered vertical lines indicate positions of the SNPs analysed in NRF-1. Haploview plot showing pairwise LD (D' values) for all 15 SNPs based on genotypes of 401 HD patients of the study. Each square plots the level of LD between a pair of SNPs, comparisons between neighboring SNPs are arranged along the first line under the names of the SNPs. Dark grey coloring indicates strong LD, medium grey shading indicates less strong LD, light grey indicates intermediate LD, and white indicates weak LD. LD blocks are framed in black and were classified according to Gabriel et al. (2002).
Mentions: In our cohort of 401 HD patients, the expanded HTT allele accounts for nearly 73% of the variance in motor AO (R2 = 0.729) and shows a highly significant influence on the AO (p < 0.0001). Multiple regression models were used to test all SNPs for association with the AO. Of these, four showed a nominal p-value < 0.05 (Table 2). For NRF-1, addition of the intronic variations rs7781972 and rs6949152 showed an association with the motor AO. Inclusion of the rs7781972 genotypes in the model increased the R2 statistic from 0.729 to 0.733 in both the dominant and the additive model (p = 0.017 and p = 0.011, Table 2). Inclusion of the rs6949152 genotypes increased the R2 from 0.729 to 0.734 (p = 0.004) according to the dominant model and to 0.733 (p = 0.013) in the additive model (Table 2). Examining linkage disequilibrium (LD) among the 15 NRF-1 variations revealed, that the variations rs10275661, rs10225103, rs7781972, rs10268267, rs6962005 and rs6949152 in IVS1 were in high LD in the cohort (D' = 1.0, r2 = 0.87-0.92). In 3' direction the LD breaks down, and a second block of very strong LD (D' = 1.0, r2 ≥ 0.98) is observed for rs10231985, rs11487138 and rs11761434. The remaining SNPs covering exon 2 to IVS10 (rs1882094, rs3735006, rs1962039, rs2402970, rs6948697 and rs10500120) showed lower LD coefficients (D') and r2 values (Figure 1).

Bottom Line: In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD.When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany. larissa.arning@rub.de.

ABSTRACT

Background: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

Results: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

Conclusions: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

No MeSH data available.


Related in: MedlinePlus