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Sci Rep. 2017 Jan 17;7:40668. doi: 10.1038/srep40668.
Alzheimer's disease affects tens of millions of people worldwide and its prevalence continues to rise. It is caused by a combination of a subject's heredity, environment, lifestyle, and medical condition. The most significant genetic risk factor for late onset Alzheimer's disease is a variant of the apolipoprotein E gene, APOE4. Here we show that the single nucleotide polymorphism rs429358 that defines APOE4 is located in a short sequence motif repeated several times within exon 4 of apolipoprotein E, reminiscent of the structure of transcriptional enhancers. A JASPAR database search predicts that the T to C transition in rs429358 generates a binding motif for nuclear respiratory factor NRF1. This site appears to be part of a binding site cluster for this transcription factor on exon 4 of APOE. This de novo NRF1 binding site has therefore the potential to affect the expression of multiple genes in its genomic vicinity. Our in silico analysis, suggesting a novel function for APOE4 at the DNA level, offers a potential mechanism for the observed tissue specific neurodegeneration and the role of environmental factors in Alzheimer's disease etiology.
阿尔茨海默病影响着全球数千万人，其患病率还在持续上升。它是由患者的遗传、环境、生活方式和医疗状况等多种因素共同作用导致的。晚发性阿尔茨海默病最大的遗传风险因素是载脂蛋白 E 基因（APOE）的一个变体 APOE4。在这里，我们发现，定义 APOE4 的单核苷酸多态性 rs429358 位于载脂蛋白 E 外显子 4 中重复多次的短序列基序内，类似于转录增强子的结构。JASPAR 数据库搜索预测，rs429358 中的 T 到 C 转换会产生核呼吸因子 NRF1 的结合基序。该位点似乎是 APOE 外显子 4 上该转录因子结合位点簇的一部分。因此，这个新的 NRF1 结合位点有可能影响其基因组附近多个基因的表达。我们的计算机分析表明，APOE4 在 DNA 水平上具有新的功能，为观察到的组织特异性神经退行性变以及环境因素在阿尔茨海默病发病机制中的作用提供了一种潜在机制。
