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

描述（由申请人提供）：低密度脂蛋白胆固醇（LDL-c）和高密度脂蛋白胆固醇（HDL-c）水平高是冠状动脉疾病（CAD）的独立危险因素。本应用程序指导阶段的第一个目标是通过完成对大一期样本的全基因组关联扫描的荟萃分析，以及对二期样本的随访，确定与HDL-c， LDL-c和甘油三酯水平相关的新基因。这种方法最近在全基因组显著阈值上成功地鉴定了七个与HDL-c、LDL- c或甘油三酯相关的新基因区域。为了进一步探索七个新基因区域以及在第一个目标中发现的任何新基因，第二个目标提出对1600个个体的相关区域内的基因以及不包含基因的关联信号进行全面的重测序，这些基因可能来自强生物学候选基因的100 kb。这种方法的目标是发现影响远端基因表达的远程调控元件的新特征，这将作为该奖项独立阶段的首要目标进行探索。该奖项指导阶段的最终目标是对具有极端性状值的个体的靶向外显子和脂质相关信号附近的保守区域进行重测序，以识别罕见的、破坏性的单核苷酸多态性或拷贝数变异。这些破坏性的变化可能提供有价值的线索，表明在一个潜在的大区域中哪个基因可能参与脂质代谢，这是对典型范例的逆转，以识别包含相关孟德尔疾病的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来自1000基因组计划的信息来估算和测试与脂质水平相关的约1000万个snp，编组相关区域的相关变异，并识别远程调控元件的特征。相关性（见说明书）：与HDL-c、LDL-c和甘油三酯水平相关的新基因和功能元件的鉴定可能对我们对心脏病机制的理解产生重大影响，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.