Rs7665116 is located in an intronic region of the peroxisome proliferator-activated receptor gamma coactivator 1A gene, which codes for the protein PGC-1α. The PGC-1 α protein is involved in the regulation of mitochondrial biogenesis, thermogenesis, and molecular mechanisms responsible for cellular respiration. PGC-1 α has also been implicated in the pathogenesis of Huntington’s disease, as mutant huntingtin protein in HD patients inhibits the PGC-1α system. The G polymorphism of the rs7665116 SNP has been associated with a three to five year delay in the age of onset of Huntington’s disease relative to the wildtype A allele.
The rs7665116 SNP is located at the 3’ end of intron 2 of PPARGC1A, in a highly conserved region of the gene. Though the majority of the variance in age of onset of Huntington’s disease is explained by the length of the CAG repeat in the HTT gene, a small portion of the variance (~4.3%) in age of onset is explained by rs7665116. The CAG repeat length is causative of Huntington’s disease,
One study conducted on a cohort of 854 European individuals (401 cases and 453 controls) revealed that the G variant of the rs76651116 SNP was associated with a delay in HD onset (p=0.0389 in the additive model and p=0.0112 in the dominant model). The association was particularly strong in the Italian population of participants, which comprised 312 of the 854 individuals (p=0.0172 in the additive model and p=0.0045 in the dominant model). For the rest of the population, the association was not statistically significant. Further studies will be necessary to determine significance in non-Italian populations. [PMID 21211002
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Another study was conducted on a cohort of 400 German patients to determine various genetic modifiers of Huntington’s disease in order to create a multivariable model explaining the variance in age of onset of the disease. The transcriptional factors nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) regulate the are also implicated in mitochondrial biogenesis, and SNPs in these genes, along with rs7555116, can explain 4.8% of the additional residual variance in the age of onset of the loss of motor coordination symptom of Huntington’s disease through a gene-gene interaction model. The exact mechanism for these interactions remains unknown, and the experiment has yet to be replicated and corrected for multiple hypothesis testing in order to more clearly explain how NRF-1, TFAM, and PGC-1 α interact to affect Huntington’s age of onset. In general, this study underscores role of impaired mitochondrial function in the pathogenesis of Huntington’s, suggesting that upstream transcriptional factors of PCG1-1 α may be useful targets for treating HD. [PMID 21595933]
One study conducted on a cohort of 234 (155 controls and 79 cases) Huntington’s patients of Italian descent demonstrated that the age of onset increased depending on the genotype of rs7665116. For patients with an A/A genotype, age of onset was on average 45.08 years, while A/G patients were 48.75, and G/G patients began to show symptoms at age 49.09. Statistical significance was maintained after the application of the Bonferroni correction (p<0.02 for the additive model and p<0.005 for the dominant model). [PMID 19133136]
[PMID 19200361] PGC-1alpha as modifier of onset age in Huntington disease.
[PMID 22589246] A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset.
[PMID 22825315] Population stratification may bias analysis of PGC-1alpha as a modifier of age at Huntington disease motor onset.
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