Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.
Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.
复制标题
DOI：
10.1002/ajmg.b.30973
复制
发表时间：
2010-01-05
期刊：
影响因子：
--
通讯作者：
Lahiri DK
中科院分区：
文献类型：
--
作者：
Maloney B;Ge YW;Petersen RC;Hardy J;Rogers JT;Pérez-Tur J;Lahiri DK
载脂蛋白E（ApoE）水平的变化与阿尔茨海默病（AD）的风险和进展有关。我们的小组以前比较和对比了小鼠和人类ApoE基因（APOE）启动子序列的启动子，发现了显着的相似性和显着的差异，表明APOE启动子在人类疾病中的作用的重要性。我们在此研究了人类APOE启动子区域内的三个特异性单核苷酸多态性，具体是+1转录起始位点上游的−491（A/T）、−427（T/C）和−219（G/T）。-219和-491多态性变异与AD的发生有显著相关性，而-491AA即使在按APOEε4等位基因分层时也有显著风险。我们还显示了在神经元细胞培养中对报告基因表达的显著影响，并且值得注意的是，这些影响被细胞的种属来源所修饰。-491和-219多态性除了具有任何独立的活性外，还可能具有相互作用。DNA-蛋白质相互作用在每个多态状态之间不同。我们建议SP1和加塔作为调控-491和-219多态性位点的候选者。这项工作的意义在于绘制之间的联系APOE启动子多态性与AD的功能启动子活性差异和DNA-蛋白质相互作用的细胞培养为基础的测定的具体变化。总之，这些结果表明，APOE表达水平是AD的一个危险因素，与APOEε4等位基因状态无关。
Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer’s disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter’s role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at −491 (A/T), −427 (T/C), and at −219 (G/T) upstream from the +1 transcription start site. The −219 and −491 polymorphic variations have significant association with instance of AD, and −491AA has significant risk even when stratified for the APOEε4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The −491 and −219 polymorphisms may have an interactive effect in addition to any independent activity. DNA–protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the −491 and −219 polymorphic sites. This work’s significance lies in drawing connection among APOE promoter polymorphisms’ associations with AD to functional promoter activity differences and specific changes in DNA–protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEε4 allele status.
登录
查看更多内容
DOI：
10.1016/s0736-5748(03)00067-4
发表时间：
2003-08-01
影响因子：
1.8
作者：
Atkins, DS;Basha, MR;Zawia, NH
通讯作者：
Zawia, NH
影响因子：
20.3
作者：
Gregory, RC;Taxman, DJ;Wojchowski, DM
通讯作者：
Wojchowski, DM
影响因子：
--
作者：
Flück, CE;Miller, WL
通讯作者：
Miller, WL
影响因子：
2.8
作者：
Ghosh, C;Song, W;Lahiri, DK
通讯作者：
Lahiri, DK
影响因子：
9.9
作者：
Hall, K;Murrell, J;Hendrie, H
通讯作者：
Hendrie, H