Hsu Michelle, Dedhia Mehek, Crusio Wim E, Delprato Anna
Department of Research and Education, BioScience Project, Wakefield, MA, 01880, USA.
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, UMR, CNRS and University of Bordeaux, UMR 5287, Pessac cedex, Aquitaine, 33615, France.
F1000Res. 2019 Apr 5;8:387. doi: 10.12688/f1000research.18671.2. eCollection 2019.
The gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the gene: , , and . The allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the allele in order to identify possible sex-related differences that may be relevant to AD. Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of in -positive individuals. The number of these genes was much higher in -positive females than in -positive males, who in turn had more of such genes than -negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain areasex genotype for PSEN2, a risk factor gene for AD. Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of with respect to sex differences and AD.
该基因编码载脂蛋白ε（ApoE），这是一种与脂质结合形成脂蛋白的蛋白质，这些脂蛋白通过血液循环来包裹和运输胆固醇及脂质。该基因至少有三种不同的等位基因：ε2、ε3和ε4。ε4等位基因会以剂量依赖的方式增加个体患晚发性阿尔茨海默病（AD）的风险。已有报道称，在AD易感性、发病年龄和症状进展方面存在性别差异，女性比男性受影响更大。在本研究中，我们采用系统生物学方法来检查携带ε4等位基因的老年女性和男性大脑中的基因表达模式，以确定可能与AD相关的性别差异。基于相关性分析，我们在携带ε4等位基因的个体中鉴定出大量表达模式与ε4相似的基因。这些基因在携带ε4等位基因的女性中数量远高于携带ε4等位基因的男性，而携带ε4等位基因的男性又比ε4阴性对照组有更多此类基因。我们的研究结果还表明，神经连接蛋白家族成员CNTNAP2基因存在显著的性别基因型相互作用，以及AD风险因子基因PSEN2存在脑区性别*基因型的显著相互作用。使用基因本体论（GO）术语分类、通路富集和差异表达分析对这些基因进行分析，支持了ε4在性别差异和AD方面具有转录作用的观点。
