APOE Gene-Based Haplotype Study in Alzeheimer's Disease

描述（由申请人提供）：载脂蛋白E基因（APOE）的e4等位基因是迟发性阿尔茨海默病（AD）的遗传风险因素。单独的APOE-ε 4既不必要也不足以导致AD。其他遗传和环境因素也可能在改变APOE相关的AD风险方面发挥作用。最近，研究表明APOE启动子区的单核苷酸多态性（SNP）与AD风险增加相关。这些APOE SNPs被进一步证明可以调节APOE的表达。因此，APOE启动子区和非编码区的SNP可能影响APOE的转录水平，从而增加AD的风险。本提案的目标是确定APOE单倍型和影响APOE表达和AD风险的关键非编码SNP，如APOE-ε 4所赋予的。将开发一种基于基因的单倍型方法来确定AD病例和对照样本中每个个体的APOE单倍型。将比较AD病例与对照组的APOE单倍型频率，并对APOE-e4等位基因状态进行分层（ε 4阳性与ε 4阴性），以评估AD单倍型的独立性。将选择在AD中过度代表或代表不足的单倍型并进行表达研究。将通过测量具有不同APOE单倍型的细胞中的mRNA水平来评价APOE表达水平。将鉴定这些单倍型中调节APOE表达的关键SNP等位基因。具体目标是：1.从散发性AD病例和对照的大样本中构建基于APOE基因的单倍型2.分析APOE单倍型与AD的相关性。3.建立APOE表达水平与单倍型之间的关联。4.从候选单倍型中鉴定影响APOE表达的关键SNPs。

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.