Zhang Deng-Feng, Li Jin, Wu Huan, Cui Yue, Bi Rui, Zhou He-Jiang, Wang Hui-Zhen, Zhang Chen, Wang Dong, Kong Qing-Peng, Li Tao, Fang Yiru, Jiang Tianzi, Yao Yong-Gang
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
Neuropsychopharmacology. 2016 Mar;41(4):1034-45. doi: 10.1038/npp.2015.232. Epub 2015 Aug 5.
The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.
免疫反应在阿尔茨海默病（AD）中高度活跃。确定免疫基因对AD的遗传风险可能为这种神经退行性疾病的预后、诊断和治疗提供重要见解。在本研究中，我们在中国队列中对欧洲人鉴定出的与AD相关的顶级免疫基因进行了基因筛查，随后进行了一项多阶段研究，重点关注补体因子H（CFH）基因。通过磁共振成像扫描评估风险单核苷酸多态性（SNP）对AD相关神经影像内表型的影响，并在老年和AD脑组织及AD细胞模型中测量其对AD脑脊液生物标志物（CSF）和CFH表达变化的影响。我们的结果表明，欧洲人报道的与AD相关的顶级免疫基因（CR1、CD33、CLU和TREML2）在中国人群中的影响较弱，而CFH显示出较强的影响。特别是，rs1061170（P(meta)=5.0×10(-4)）和rs800292（P(meta)=1.3×10(-5)）与AD表现出强烈关联，并在多个全球样本集中得到证实（4317例病例和16795例对照）。Rs1061170（P=2.5×10(-3)）和rs800292（P=4.7×10(-4)）风险等位基因携带者在年轻时内嗅皮层厚度增加，且随着疾病进展萎缩率更高。Rs800292风险等位基因携带者的CSF tau和Aβ水平更高，且认知功能严重下降。受风险等位基因影响的CFH表达水平在AD脑和细胞模型中升高。这些综合分析表明，CFH是AD中的一个重要免疫因子，影响早期和疾病进展过程中的多种病理变化。
