Genetic Variants Associated with HDL and LDL Cholesterol, and Triglyceride Levels

描述(由申请人提供)：高水平的低密度脂蛋白胆固醇(低密度脂蛋白-c)和低水平的高密度脂蛋白胆固醇(高密度脂蛋白-c)是冠状动脉疾病(CAD)的独立危险因素。该应用的指导阶段的第一个目标是通过在大的阶段1样本中完成全基因组关联扫描的荟萃分析，以及在阶段2样本中的跟踪，识别与高密度脂蛋白-c、低密度脂蛋白-c和甘油三酯水平相关的新基因。该方法最近在全基因组范围内成功地识别了与高密度脂蛋白-c、低密度脂蛋白-c或甘油三酯相关的七个新的基因区域。为了进一步探索这七个新基因区域以及在第一个目标中发现的任何新基因，第二个目标建议对1600个个体进行全面的重新测序，以寻找相关区域内的基因以及不包含某个基因的关联信号，这些关联信号可以是来自强生物候选基因的100kb。这种方法的目标是发现影响远距离基因表达的远程调控元件的新签名，这将作为该奖项独立阶段的第一个目标进行探索。在该奖项的指导阶段，最终目标是对具有极端性状值的个体的脂质相关信号附近的靶向外显子和保守区重新排序，以识别罕见的破坏性单核苷酸多态或拷贝数变体。这些破坏性的变化可能提供关于潜在大区域中的哪个基因可能参与脂代谢的宝贵线索，这是对典型范式的逆转，以确定包含相关孟德尔疾病罕见破坏性突变的基因中的常见变异。该奖项独立阶段的最终目标是使用1000基因组计划的信息来归类和测试与血脂水平相关的约1000万个SNP，对相关区域的相关变异进行分类，并确定远程调控元件的特征。相关性(参见说明)：识别与高密度脂蛋白、低密度脂蛋白和甘油三酯水平相关的新基因和功能元件可能会对我们理解心脏病的机制产生重大影响，并有可能导致新的治疗方法。

DESCRIPTION (provided by applicant): High levels of LDL cholesterol (LDL-c) and low levels of HDL cholesterol (HDL-c) are independent risk factors for coronary artery disease (CAD). The first aim of the mentored-phase of this application is to identify novel genes associated with HDL-c, LDL-c, and triglyceride levels by completing meta-analyses for genome-wide association scans in large stage 1 samples, together with follow-up in stage 2 samples. This approach has recently been successful in identifying seven novel gene regions associated with HDL-c, LDL- c or triglycerides at a genome-wide significant threshold. To further explore the seven novel gene regions as well as any novel genes identified in the first aim, the second aim proposes comprehensive re-sequencing of 1600 individuals for genes within the associated regions as well as association signals that do not contain a gene, which can be 100 kb from strong biological candidate genes. The goal of this approach is to uncover novel signatures of long-range regulatory elements that influence expression of distant genes, and this will be explored as the first aim during the independent phase of the award. The final aim during the mentored- phase of the award is to re-sequence targeted exonic and conserved regions near lipid-associated signals in individuals with extreme trait values to identify rare, disruptive single nucleotide polymorphisms or copy number variants. These disruptive changes may provide valuable clues about which gene in a potentially large region may be involved in lipid metabolism, a reversal of the typical paradigm to identify common variants in genes that contain rare disruptive mutations for related Mendelian disorders. The final aim for the independent phase of the award is to use information from the 1000 Genomes Project to impute and test ~10 million SNPs for association with lipid levels, catalog associated variants in associated regions and identify signatures of long-range regulatory elements. RELEVANCE (See Instructions): The identification of novel genes and functional elements associated with HDL-c, LDL-c and triglyceride levels is likely to have a significant impact on our understanding of the mechanisms of heart disease and has the potential to lead to new treatments.