发现CTSH稀有异义变异rs2289702在我国人群中展现出AD发病的保护效应，并阐明了其作用机制的数据集

前期，通过对我国早发及家族性AD患者进行全外显子组测序，发现多个国人特异的与AD风险相关的稀有变异位点。进一步分析发现，组织蛋白酶基因CTSH的一个稀有异义变异rs2289702，在我国人群中展现出AD发病的保护效应，该效应在欧洲人群也得到验证，是一个不同人群中的共有的AD保护性变异。CTSH基因在AD病人脑组织中呈现高表达趋势，在AD小鼠模型中，该基因表达水平与Aβ斑块沉积、tau蛋白过度磷酸化水平正相关。对该变异开展的功能基因组学分析和细胞水平实验表明，rs2289702是个调控性变异位点，能够影响转录因子ZPF69B与CTSH基因启动子区结合，从而下调CTSH基因表达。机制研究发现，敲除CTSH可以促进小胶质细胞吞噬Aβ42的能力。这些结果提示，由rs2289702变异导致的CTSH低水平表达是该变异对于AD发病具有保护性效应的一个原因；干预CTSH表达水平，有望是缓解AD发生的一种方式

Previously, whole-exome sequencing was performed on early-onset and familial Alzheimer's disease (AD) patients in China, and multiple Chinese population-specific rare variant loci associated with AD risk were identified. Further analysis revealed that a rare missense variant rs2289702 in the cathepsin H gene CTSH exhibited a protective effect against AD onset in the Chinese population, and this effect was validated in European populations, making it a shared AD-protective variant across different populations. The CTSH gene shows a trend of elevated expression in brain tissues of AD patients. In AD mouse models, the expression level of this gene is positively correlated with Aβ plaque deposition and the level of hyperphosphorylated tau protein. Functional genomics analysis and cell-based experiments targeting this variant demonstrated that rs2289702 is a regulatory variant locus that affects the binding of transcription factor ZPF69B to the promoter region of the CTSH gene, thereby downregulating the expression of the CTSH gene. Mechanistic studies revealed that knockout of CTSH enhances the phagocytic capacity of microglia for Aβ42. These findings suggest that the low expression of CTSH caused by the rs2289702 variant is one of the reasons for the protective effect of this variant against AD onset; modulating the expression level of CTSH holds promise as a potential strategy to mitigate the development of AD.

搜集汇总

背景与挑战

背景概述

该数据集聚焦于CTSH基因rs2289702变异对阿尔茨海默病的保护作用机制研究，包含实验验证数据和分子机制分析结果。研究证实该变异在中国人群中具有保护效应，并通过调控CTSH表达水平影响Aβ肽段的吞噬过程。