PGC-1α 编码区的单核苷酸多态性是影响大型欧洲队列亨廷顿病发病年龄的一个男性特异性修饰因子。
A single nucleotide polymorphism in the coding region of PGC-1α is a male-specific modifier of Huntington disease age-at-onset in a large European cohort.
机构信息
Neurology, Ulm University, 89081 Ulm, Germany.
出版信息
BMC Neurol. 2014 Jan 2;14:1. doi: 10.1186/1471-2377-14-1.
BACKGROUND
Genetic modifiers are important clues for the identification of therapeutic targets in neurodegenerative diseases. Huntington disease (HD) is one of the most common autosomal dominant inherited neurodegenerative diseases. The clinical symptoms include motor abnormalities, cognitive decline and behavioral disturbances. Symptom onset is typically between 40 and 50 years of age, but can vary by several decades in extreme cases and this is in part determined by modifying genetic factors. The metabolic master regulator PGC-1α, coded by the PPARGC1A gene, coordinates cellular respiration and was shown to play a role in neurodegenerative diseases, including HD.
METHODS
Using a candidate gene approach we analyzed a large European cohort (n = 1706) from the REGISTRY study for associations between PPARGC1A genotype and age at onset (AO) in HD.
RESULTS
We report that a coding variant (rs3736265) in PPARGC1A is associated with an earlier motor AO in men but not women carrying the HD mutation.
CONCLUSIONS
These results further strengthen the evidence for a role of PGC-1α in HD and unexpectedly suggest a gender effect.
背景
遗传修饰物是鉴定神经退行性疾病治疗靶点的重要线索。亨廷顿病（HD）是最常见的常染色体显性遗传性神经退行性疾病之一。其临床症状包括运动异常、认知能力下降和行为障碍。发病通常在 40 到 50 岁之间，但在极端情况下可以相差几十年，这在一定程度上取决于修饰基因。代谢主调控因子 PGC-1α 由 PPARGC1A 基因编码，协调细胞呼吸，被证明在包括 HD 在内的神经退行性疾病中发挥作用。
方法
我们使用候选基因方法分析了 REGISTRY 研究中的一个大型欧洲队列（n=1706），以研究 PPARGC1A 基因型与 HD 发病年龄（AO）之间的关联。
结果
我们报告称，PPARGC1A 中的一个编码变异（rs3736265）与携带 HD 突变的男性的运动 AO 提前有关，但与女性无关。
结论
这些结果进一步加强了 PGC-1α 在 HD 中的作用的证据，并且出人意料地表明存在性别效应。
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