Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease.
Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease.
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DOI：
10.1186/1750-1326-6-1
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发表时间：
2011-01-06
影响因子：
15.1
通讯作者：
Nguyen HP
中科院分区：
文献类型：
--
作者：
Che HV;Metzger S;Portal E;Deyle C;Riess O;Nguyen HP
亨廷顿病（HD）是由亨廷顿蛋白中超过35个单位的多聚谷氨酰胺扩增引起的。这种扩增的重复序列长度与发病年龄（AAO）呈负相关，然而，除了扩增的CAG重复序列长度外，其他遗传因素被认为会影响HD的病程和AAO。到目前为止，其中，编码PCG-1α（PPARGC 1A）的基因被证明在两个独立的，但很小的群体中修饰AAO。PGC-1α参与诱导调节线粒体生物合成和氧化应激防御的各种机制。此外，一些研究已经将其功能和/或其表达的损伤与HD发病机制联系起来。由于关联研究中不同修饰物的鉴定在很大程度上取决于观察人群的规模，我们研究了PPARGC 1A中9种不同的单核苷酸多态性（SNP），以在800多名欧洲HD患者中复制疾病修饰作用，并鉴定与HD中AAO的关联。两个SNPs，一个在启动子和一个在基因的转录区，显示出对AAO的显着影响。而位于转录基因区域的SNP rs7665116（g.38570C）的次要等位基因与疾病发作的延迟相关，尤其是在具有意大利血统的HD患者中，SNP rs 2970870（g.-38570 C）的次要等位基因与疾病发作的延迟相关。1437 C）导致HD在其纯合状态下较早发作。此外，单倍型块2的全球测试，其中包括基因转录区的主要部分，揭示了块2单倍型和疾病发作之间的关联。因此，我们的研究结果表明一个基因内的两个SNP对AAO的相反修饰影响，并支持PGC-1α功能障碍参与HD病理学的观点。
Huntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1α (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1α is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD. Two SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset. Therefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1α dysfunction is involved in HD pathology.
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通讯作者：
Spiegelman, BM
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