Yao Lifen, Li Keshen, Zhang Liming, Yao Songpo, Piao Zhongyuan, Song Lin
Department of Neurology, The first affiliated hospital of Harbin Medical University, Harbin 150001, China.
Brain Res. 2009 Sep 29;1291:133-9. doi: 10.1016/j.brainres.2009.07.034. Epub 2009 Jul 23.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been described to have a role in the modulation of various genes involved in Abeta homeostasis, inflammation, and energy metabolism, making it a candidate gene for risk of Alzheimer's disease (AD). A functional polymorphism in exon 2 of the PPAR-gamma gene has been related to AD, but the effects are inconsistent across studies. To determine the role of PPAR-gamma in genetic susceptibility to AD in a representative Chinese sample, we genotyped 362 AD patients and 370 healthy controls for PPAR-gamma Pro12Ala polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. We also examined the potential impact of this polymorphism on plasma level of soluble receptor for advanced glycation end products (sRAGE), a decoy receptor whose reduction has been associated with a higher risk of AD. Our results suggest that PPAR-gamma Pro12Ala polymorphism was not associated with an increased risk of AD in the overall sample. Stratification analysis revealed that the PPAR-gamma Pro/Ala genotype may be associated with the development of early-onset AD in the individuals without APOE epsilon4 allele (OR=3.76, 95% CI=1.10-12.84; p=0.03), but this association became insignificant after Bonferroni correction (p (corr)=0.10). Moreover, in the subgroup of APOE epsilon4 noncarriers, Kaplan-Meier survival analyses indicated that AD patients with the Pro/Ala genotype presented with disease onset 4.6 years earlier than carriers of Pro/Pro genotype. Further investigation revealed that AD patients carrying Pro/Ala genotype had significantly lower plasma sRAGE levels than patients with Pro/Pro genotype. These findings suggest that the functional PPAR-gamma Pro12Ala polymorphism may modify the age at onset of AD.
过氧化物酶体增殖物激活受体γ（PPAR-γ）已被描述在调节参与β淀粉样蛋白稳态、炎症和能量代谢的各种基因中发挥作用，这使其成为阿尔茨海默病（AD）风险的候选基因。PPAR-γ基因外显子2中的一个功能性多态性与AD相关，但不同研究的结果并不一致。为了确定PPAR-γ在具有代表性的中国样本中对AD遗传易感性的作用，我们采用聚合酶链反应-限制性片段长度多态性方法，对362例AD患者和370例健康对照进行了PPAR-γ Pro12Ala多态性基因分型。我们还研究了这种多态性对晚期糖基化终产物可溶性受体（sRAGE）血浆水平的潜在影响，sRAGE是一种诱饵受体，其水平降低与AD风险增加有关。我们的结果表明，在总体样本中，PPAR-γ Pro12Ala多态性与AD风险增加无关。分层分析显示，在没有APOE ε4等位基因的个体中，PPAR-γ Pro/Ala基因型可能与早发性AD的发生有关（OR=3.76，95%CI=1.10-12.84；p=0.03），但在Bonferroni校正后这种关联变得不显著（p（校正）=0.10）。此外，在APOE ε4非携带者亚组中，Kaplan-Meier生存分析表明，Pro/Ala基因型的AD患者发病时间比Pro/Pro基因型携带者早4.6年。进一步研究发现，携带Pro/Ala基因型的AD患者血浆sRAGE水平显著低于Pro/Pro基因型患者。这些发现表明，功能性PPAR-γ Pro12Ala多态性可能会改变AD的发病年龄。
