LDLR Genetics, Splicing and AD Risk

描述（由申请人提供）：识别显著改变关键蛋白质功能的遗传变异，为相关疾病过程和可能的治疗提供见解。低密度脂蛋白受体（LDLR）在这方面是值得注意的，因为LDLR突变是家族性高胆固醇血症的主要原因，即单个LDLR等位基因的丢失会导致低密度脂蛋白胆固醇水平增加约100%。尽管LDLR snp及其单倍型与胆固醇水平的改变有关，但改变LDLR功能的特定snp尚未被确定。功能性LDLR变异可能有助于了解与胆固醇升高相关的疾病，例如阿尔茨海默病（AD）。事实上，脂蛋白e基因的apoE4等位基因是胆固醇和AD的一个强有力的遗传因素。虽然载脂蛋白e与阿尔茨海默病的淀粉样蛋白沉积有关，但载脂蛋白e在胆固醇传递和体内平衡中的作用更为广泛；apoE4作为介导脂蛋白摄取的细胞表面受体LDL家族的配体，与LDL-胆固醇升高有关。本研究的重点是一个全球性的假设，即调节LDLR剪接或表达的snp，以及由这些功能性snp定义的单倍型，与胆固醇稳态改变和阿尔茨海默病有关。因此，我们提出以下具体目标：评估LDLR snp以确定那些改变LDLR剪接和/或表达的snp。评估LDLR选择性剪接导致的LDLR蛋白的表达和功能。3. 评估LDLR基因型和单倍型与胆固醇稳态和阿尔茨海默病的关系。总的来说，这一重点方法将直接评估LDLR多态性调节LDLR剪接和表达以增加ldl -胆固醇和阿尔茨海默病几率的假设。

DESCRIPTION (provided by applicant): Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia, i.e., loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels, specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol, e.g., Alzheimer's Disease (AD). Indeed, a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease, apoE is known more widely for its role in cholesterol delivery and homeostasis; apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression, and the haplotypes defined by these functional SNPs, are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence, we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression, 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall, this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds.