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，可深入了解相关疾病过程和可能的治疗方法。低密度脂蛋白受体（LDLR）在这方面是显著的，因为LDLR突变是家族性高胆固醇血症的主要原因，即，单个LDLR等位基因的缺失导致LDL-胆固醇水平增加约100%。尽管LDLR单核苷酸多态性及其单倍型与胆固醇水平的改变有关，但改变LDLR功能的特异性单核苷酸多态性尚未确定。功能性LDLR变体可以提供对可能与胆固醇增加相关的疾病的了解，例如，阿尔茨海默病（AD）。事实上，胆固醇和AD的一个强有力的遗传因素是apoE基因的apoE 4等位基因。虽然apoE与阿尔茨海默病中的淀粉样蛋白-β（Abeta）沉积有关，但apoE因其在胆固醇递送和体内平衡中的作用而更广泛地为人所知; apoE4通过其作为介导脂蛋白摄取的LDL家族细胞表面受体的配体的作用而与LDL-胆固醇增加相关。该提案集中于调节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相关的全球假设。因此，我们提出以下具体目标：1。评价LDLR SNP以鉴定改变LDLR剪接和/或表达的那些SNP，2.评价LDLR可变剪接产生的LDLR蛋白的表达和功能。3.评价LDLR基因型和单倍型与胆固醇稳态和阿尔茨海默病的关系。总体而言，这种集中的方法将直接评估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.