APOE Gene-Based Haplotype Study in Alzeheimer's Disease

描述(申请人提供)：载脂蛋白E基因(APOE)的e4等位基因是晚发性阿尔茨海默病(AD)的遗传危险因素。APOE-epsilon 4本身既不是引起AD的必要条件，也不是充分条件。其他遗传和环境因素也可能在改变与载脂蛋白E相关的阿尔茨海默病风险方面发挥作用。最近，研究表明载脂蛋白E启动子区域的单核苷酸多态(SNPs)与AD的风险增加有关。进一步证明这些APOE单核苷酸多态能够调节APOE的表达。因此，APOE启动子和非编码区的SNP可能影响APOE的转录水平，从而增加AD的风险。这项建议的目的是确定APOE单倍型和影响APOE表达和AD风险的关键非编码SNP，如APOE-epsilon 4所赋予的那样。我们将开发一种基于基因的单倍型方法来确定AD患者和对照样本中每个个体的APOE单倍型。将比较AD患者和对照组的APOE单倍型频率，并将APOE-e4等位基因状态分层(epsilon 4阳性与epsilon 4阴性)，以评估AD单倍型的独立性。在AD中表达过高或表达不足的单倍型将被选择并进行表达研究。将通过测量不同APOE单倍型细胞中的mRNA水平来评估APOE的表达水平。这些单倍型中调节载脂蛋白E表达的关键SNP等位基因将被识别出来。本研究的具体目的是：1.从大量的散发性AD患者和对照中构建基于APOE基因的单倍型。2.分析载脂蛋白E单倍型与AD的关系。3.建立APOE表达水平与单倍型之间的关联。4.从影响APOE表达的候选单倍型中识别关键的SNP。

DESCRIPTION (provided by applicant): The e4 allele of the apolipoprotein E gene (APOE) is a genetic risk factor for late onset Alzheimer's disease (AD). APOE-epsilon4 alone is neither necessary nor sufficient to cause AD. Other genetic and environmental factors are also likely to play a role in modifying the APOE-related risk of developing AD. Recently, studies have suggested an association of single nucleotide polymorphisms (SNPs) in the promoter region of APOE with increased risk for AD. These APOE SNPs were further demonstrated to modulate APOE expression. Thus, SNPs in both the promoter and non-coding regions of APOE may influence transcriptional level of APOE thereby adding to the risk in AD. The goal of this proposal is to identify APOE haplotypes and critical non-coding SNPs that influence APOE expression and AD risk as conferred by the APOE-epsilon4. A gene-based haplotype method will be developed to determine APOE haplotypes from each individual in our AD cases and controls sample. The APOE haplotype frequencies will be compared in AD cases vs. controls, and APOE-e4 allele status will be stratified (epsilon4 positive vs. epsilon4 negative) to assess the independence of the haplotypes in AD. Haplotypes, either over- or under-represented in AD, will be selected and subjected to expression studies. APOE expression levels will be evaluated by measuring mRNA levels in cells with different APOE haplotypes. Critical SNP alleles within these haplotypes that modulate APOE expression will be identified. The specific aims are to: 1. Construct APOE gene-based haplotypes from a large sample of sporadic AD cases and controls. 2. Analyze the association between APOE haplotypes and AD. 3. Establish association between APOE expression level and haplotypes. 4. Identify critical SNPs from candidate haplotypes that affect APOE expression.