血脂水平已成为一系列心血管疾病和代谢疾病的可检测临床指标和疾病风险的重要预测因子。载脂蛋白APOA1/C3/A4/A5基因簇是血脂代谢和心血管疾病相关的重要基因区域。本课题拟对该基因区域在高通量测序系统检测遗传变异的基础上，进行与血脂水平和冠状动脉粥样硬化发生的复杂疾病和表型相结合的关联分析。通过分别针对常见变异、罕见变异和突变的多种方法的综合分析，试图精细定位导致了统计关联性的功能性常见变异，揭示由于罕见变异作用而常见变异无法解释的遗传贡献，发现中国人群中新的基因突变，并在大样本中验证分析结果和开展初步的功能实验。课题结果能更深入地认识APOA1/C3/A4/A5基因簇中血脂的遗传决定因素和冠状动脉粥样硬化发生风险的分子遗传基础。

Blood lipids have become the measurable clinical index and the important disease-risk predictors for a set of cardiovascular diseases and metabolic diseases. The APOA1/C3/A4/A5 gene cluster is a key genomic region involved in blood lipid metabolism and cardiovascular diseases. The present study intends to systematically investigate the genetic variations in the gene cluster region using high-throughput sequencing method, and to conduct detailed association analyses for complex disease and traits combining coronary atherosclerosis with blood lipid levels. After comprehensive analyses by multiple tests for common variants, low-frequency or rare variants and novel mutations, we attempt to fine map the true common variants accounting for the statistic associations, to reveal the rare variants contributing to the missing genetic variance which is uninterpretable by common variants, and to identify novel mutations in Chinese population. The candidate variants after extensive screening will be validated in an independent large sample and by preliminary functional assays in cell lines. The results of the study will provide us insight into the genetic determinants of blood lipids and the genetic risk factors for the development of coronary atherosclerosis.