Medical Scientist Training Program, Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA,
Hum Genet. 2014 Jan;133(1):85-93. doi: 10.1007/s00439-013-1354-8. Epub 2013 Sep 12.
Late-onset Alzheimer's disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer's disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD's genetic etiology. Subsets of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid-calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.
迟发性阿尔茨海默病（LOAD）的病因复杂，呈寡基因遗传，遗传异质性较大。我们研究了阿尔茨海默病（AD）通路中基因间的遗传相互作用对淀粉样蛋白-β（Aβ）沉积的影响，这种沉积通过 PiB 或 AV-45 配体正电子发射断层扫描（PET）来测量，以帮助理解 LOAD 的遗传病因。阿尔茨海默病神经影像学倡议（ADNI）队列的子集用于发现和两项独立的验证分析。在所有三个独立的 ADNI 数据集都证实了 RYR3 和 CACNA1C 之间存在显著的相互作用。这两个基因都编码在大脑中表达的钙通道。这里显示的结果支持先前的动物研究，表明这些钙通道之间的相互作用在淀粉样蛋白形成中起作用，并表明该疾病的病理级联可能通过淀粉样蛋白-钙轴的相互作用而改变。未来专注于这些关系的机制的工作可能为临床干预的靶点提供信息。
