PGC-1alpha 多态性与帕金森病发病年龄及风险的关联。
Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease.
机构信息
Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room CLS-638, Boston, MA 02215, USA.
出版信息
BMC Med Genet. 2011 May 19;12:69. doi: 10.1186/1471-2350-12-69.
BACKGROUND
Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α 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-1α. We hypothesized that the rs8192678 PGC-1α 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-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.
METHODS
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.
RESULTS
The rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α 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).
CONCLUSIONS
These data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α 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-1α in PD and longevity.
背景
过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1α 是抗氧化基因的转录共激活因子，也是线粒体生物发生的主要调节因子。帕金森病（PD）与氧化应激和线粒体功能障碍有关，最近的研究表明 PGC-1α 起作用。我们假设 rs8192678PGC-1α 单核苷酸多态性（SNP）可能影响 PD 的风险或发病年龄。在一些研究中，线粒体 SNP 的 A10398G 与 PD 的风险呈负相关。在目前的研究中，我们分析了 rs8192678 或其他 PGC-1α SNP 是否单独或与 A10398G SNP 一起影响 PD 的风险或发病年龄。
方法
通过多重探针测序分析了 378 名 PD 患者和 173 名年龄匹配的对照者的基因组 DNA 样本，然后对每个 SNP 的关联进行了统计分析，单独或与 A10398G SNP 一起进行了分析。对发病年龄小于采样年龄的情况进行了调整，并且对这两个年龄之间的观察到的依赖性进行了调整。PD 样本是作为两个独立的队列获得的，因此统计方法考虑了两个队列之间不同的采样方法，并使用 Cox 回归进行了分析，该回归在风险集定义和模型中都考虑了采样。
结果
rs8192678PGC-1α SNP 与 PD 的风险无关。然而，在对照者中观察到 PGC-1α rs8192678GG 变体与长寿相关（p=0.019）。探索性研究表明，rs6821591 的 CC 变体与早发性 PD 的风险相关（p=0.029），与 PD 的发病年龄相关（p=0.047），与长寿相关（p=0.022）。rs2970848GG 等位基因与晚发性 PD 的风险相关（p=0.027）。
结论
这些数据显示，PGC-1αSNPrs6821591 和 rs2970848 可能与 PD 的风险或发病年龄相关，PGC-1αrs8192678GG 和 rs6821591CC 变体与长寿相关。如果在其他数据集得到复制，这些发现可能对 PGC-1α 在 PD 和长寿中的作用具有重要意义。
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