基于高通量靶向测序对基因多效的载脂蛋白A1/C3/A4/A5基因簇区域致病遗传变异研究

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.

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。

本课题针对血脂代谢和心血管疾病相关的APOA1/C3/A4/A5基因簇这一重要候选基因区域，通过对有详细相关临床信息的超过2500例中国汉族人群样本进行高通量测序。课题建立了对目标连续区域用多重PCR扩增构建文库的高通量测序方法，和针对扩增子测序数据的高效数据分析流程。把常见和罕见变异分别用多种相应的分析方法与冠状动脉粥样硬化病例对照及血清TC、HDL-C、LDL-C、TG、APOA-Ⅰ和APOB水平做系统深入地关联性分析后，综合各关联分析结果及基因注释信息，筛查了该基因区域内对个血脂水平调控有重要作用的基因、功能性基因区域和关键遗传变异位点，还鉴定了与冠状动脉粥样硬化和心肌梗死相关，可成为疾病风险评估分子标志物的遗传变异位点。研究结果更深入地认识了APOA1/C3/A4/A5基因簇内血脂水平的遗传决定因素和冠状动脉粥样硬化发生风险贡献的分子遗传基础。

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