汉族人群ABCA7功能缺失突变与阿尔茨海默病的关联及其致病机制研究

Recently, loss-of-function (LOF) mutations in ATP binding cassette subfamily A member 7 (ABCA7) were identified to confer risk of Alzheimer’s disease (AD) in Caucasian. The LOF mutations increased susceptibility to late-onset Alzheimer’s disease (LOAD) with an odds ratio of 2 to 4, which was significantly stronger than that of the common ABCA7 loci in genome-wide associated studies (GWAS), suggesting ABCA7 LOF mutations represented the novel susceptibility loci for LOAD. To date, the association of ABCA7 LOF mutations with LOAD risk in Han Chinese was unclear. Here we intend to finely map ABCA7 by next-generation sequencing to identify risk variants in a larger Han Chinese cohort, especially the risk of ABCA7 LOF mutations for LOAD in Chinese. In addition, our investigation and other studies have demonstrated the ABCA7 deficiency can increase the Aβ deposition in brain. However, the role of ABCA7 LOF mutations in Aβ metabolism remains unclear. To fully elucidate the role of ABCA7 LOF mutations in AD pathogenesis, we investigate the impact of ABCA7 LOF mutations on the expression of ABCA7 in peripheral blood mononuclear cells (PBMCs), and the Aβ clearage of monocyte, as well as the correlation between ABCA7 expression and Aβ clearage. This project will uncover the possible underlying mechanism that ABCA7 LOF mutations induced AD. It will provide theoretic support for early warning and diagnosis of AD in Chinese, and also offer novel target for therapies and drug development of this disease.

最近，高加索人群二代测序研究发现ABCA7功能缺失（Loss of Function, LOF）突变是AD新的致病位点，其增加患病风险2-4倍。我们前期研究发现ABCA7基因多态性与AD的关联在不同种族间存在差异，以及ABCA7通过作用于Aβ参与AD的发病机制。目前新发现的ABCA7基因LOF突变是否与汉族人群LOAD相关，及LOF突变影响Aβ的机制尚不明确。我们在前期建立的汉族人群LOAD资源库基础上，拟对ABCA7关键区域进行二代高通量测序，重点分析LOF突变与LOAD的关联，全面阐述ABCA7遗传变异与汉族人群LOAD的关系。此外，我们拟检测外周血ABCA7表达水平，观察LOF突变是否影响ABCA7的表达，并用Aβ刺激单核细胞，研究LOF突变和ABCA7表达水平对单核细胞Aβ清除功能的影响，以阐明ABCA7基因LOF突变导致AD的发病机制，并为AD诊疗提供全新靶点。

最近，高加索人群二代测序研究发现ABCA7功能缺失（Loss of Function, LOF）突变是AD新的致病位点，其增加患病风险2-4倍。我们前期研究发现ABCA7基因多态性与AD的关联在不同种族间存在差异，以及ABCA7通过作用于Aβ参与AD的发病机制。目前新发现的ABCA7基因LOF突变是否与汉族人群LOAD相关，及ABC7导致AD的发病机制尚不明确。我们在前期建立的汉族人群LOAD资源库基础上，拟对ABCA7关键区域进行二代高通量测序，重点分析LOF突变与LOAD的关联，全面阐述ABCA7遗传变异与汉族人群LOAD的关系，我们发现了ABC7基因11个LOF位点，但在汉族人群中ABCA7基因LOF与AD并无显著性关联。我们在进一步的荟萃分析中发现，ABCA7基因多态性与AD的相关性具有显著的种族差异，除了种族间遗传背景的差异外，不同种族间样本量的差别也可能是产生差异的原因，高加索人群的样本量远大于汉族人群样本量，因此，在更大规模的样本中验证ABCA7基因变异与AD的相关性是有必要的。另外，我们发现ABC7基因变异可以影响脑脊液中Aβ的水平和变化，说明ABC7通过干预Aβ参与AD的发病机制, 进一步验证了ABC7通过影响Aβ参与AD的发病机制。

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