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Genetic analysis of polymorphisms in the kalirin gene for association with age-at-onset in European Huntington disease patients.

ABSTRACT: BACKGROUND: Huntington disease (HD) is caused by an expanded CAG repeat in the HD gene. Although the length of the CAG repeat strongly correlates with the age-at-onset (AAO), AAO in HD individuals may differ dramatically in spite of similar expanded CAG repeat lengths. Additional genetic or environmental factors are thought to influence the disease onset. Several modifier genes have been discovered so far but they do not fully explain the variability of AAO in HD. To potentially identify a novel genetic modifier, we analyzed single nucleotide polymorphisms (SNPs) in the kalirin (KALRN) gene. Kalirin is a protein crucially involved in spine plasticity and its interaction with huntingtin-associated protein-1 (HAP-1) and a potential protein dysfunction might contribute to spine pathogenesis in HD. METHODS: The selected SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and association of SNPs with AAO was investigated with the framework of linear models in an analysis of variance and covariance. RESULTS: Eleven SNPs in the kalirin gene were examined in an association study in European HD patients. The ten coding SNPs under investigation were monomorphic, whereas SNP rs10934657 in the promoter region showed a minor allele frequency >1%. An analysis of covariance together with the influence of the expanded HD allele was applied in 680 HD patients. SNP rs10934657 did not affect the AAO of the examined HD population. CONCLUSIONS: The results did not reveal an association between the analyzed kalirin polymorphisms and the AAO in HD. However, it does not exclude other SNPs of the kalirin gene as susceptible genetic modifiers.

SUBMITTER: Tsai YC

PROVIDER: S-EPMC3433364 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetic analysis of polymorphisms in the kalirin gene for association with age-at-onset in European Huntington disease patients.

Tsai Yu-Chun YC Metzger Silke S Riess Olaf O Soehn Anne S AS Nguyen Huu Phuc HP

BMC medical genetics 20120621

<h4>Background</h4>Huntington disease (HD) is caused by an expanded CAG repeat in the HD gene. Although the length of the CAG repeat strongly correlates with the age-at-onset (AAO), AAO in HD individuals may differ dramatically in spite of similar expanded CAG repeat lengths. Additional genetic or environmental factors are thought to influence the disease onset. Several modifier genes have been discovered so far but they do not fully explain the variability of AAO in HD. To potentially identify ...[more]

PMID: 22720673

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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

Genetic analysis of polymorphisms in the kalirin gene for association with age-at-onset in European Huntington disease patients.

Publications

Genetic analysis of polymorphisms in the kalirin gene for association with age-at-onset in European Huntington disease patients.

Similar Datasets

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