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Toward precision medicine: modulation of ABCA7 associated risk of Alzheimer's disease by ancestry

迈向精准医疗：通过血统调节 ABCA7 相关阿尔茨海默病风险

基本信息

批准号：
10323669
负责人：
Nicholas Lyssenko
金额：
$ 15.85万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323669
关键词：
ATP-Binding Cassette Transporters Abeta synthesis Adenosine Triphosphate Affect African African ancestry Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Asian ancestry Asian population Attenuated Binding CRISPR/Cas technology Cell Line Complex Conditioned Culture Media Cultural Diversity Data Dementia Development Diagnostic Disease East Asian Economics European Exhibits Foundations Frequencies Functional disorder Gene Frequency Genes Genetic Genetic Diseases Genetic study Goals Healthcare Human Human Genetics Individual Induced pluripotent stem cell derived neurons Lead Life Measures Metabolism Methods Minor Neurons Pathogenesis Pathology Philadelphia Play Population Proteins Research Risk Risk Factors Role Surveys System Testing Therapeutic Time Variant Work base biobank brain tissue cell repository cohort disorder control disorder risk ethnic diversity exome sequencing experience genetic variant genome sequencing genome wide association study induced pluripotent stem cell loss of function loss of function mutation male member mouse model precision medicine therapeutic development

项目摘要

Abstract Ethnic and cultural diversity offers economic and societal benefits. It also poses challenges in therapeutic development and health care provision. However, ancestry has not been taken consistently into consideration until recently, when the need for precision medicine became apparent. There is therefore lack of research into ancestral differences in disease pathology and even of well-established approaches on how to investigate such differences. Mouse models do not seem to be suitable for studies of pathophysiology by ancestry. The purpose of this study is to elucidate how much loss of adenosine triphosphate binding cassette transporter subfamily A member 7 (ABCA7) affects amyloid β (Aβ) metabolism in individuals of European, African and East Asian ancestry using human induced pluripotent stem (iPS) cell-derived neurons. ABCA7 has been implicated as a risk factor in Alzheimer's disease (AD) pathology in many genome-wide association and genome sequencing studies in European, African and, to a lesser extent, East Asian ancestry. In preliminary data, we confirm observations from genetics and show that in a cohort of approximately 145 AD and control subjects of mostly European ancestry, individuals with very low ABCA7 levels exhibited accelerated AD pathogenesis. We also show that deletion of ABCA7 using CRISPR/Cas9 in iPS cell-derived neurons from individuals of European ancestry leads to an increase in Aβ secretion. Finally, we confirm that ABCA7 loss-of-function alleles are common (~5% minor allele frequency) in African ancestry by inspecting whole-exome sequencing data from a cohort of individuals from Philadelphia in a biobank. Human genetic studies have found that loss-of-function alleles in ABCA7 in populations of European ancestry increase the risk of AD by several fold, while ABCA7 loss-of-function alleles in populations of African ancestry increase the risk of the disease by at most 80%. Based on this, we advance the hypothesis that loss of ABCA7 in African ancestry is less detrimental than in European ancestry. To test this hypothesis, we propose to delete ABCA7 in iPS cells from individuals of African and East Asian ancestry and to determine how much loss of this gene affects Aβ synthesis in iPS cell- derived neurons of these two ancestries in comparison with iPS cell-derived neurons of European ancestry. Based on the genetic studies, the prediction is that loss of ABCA7 in iPS cell-derived neurons from subjects of African ancestry will elevate Aβ production less than in iPS cell-derived neurons from European ancestry subjects. The proposed work will show whether iPS cell-derived neurons can be used to study pathophysiological differences by ancestry, conform observations from human genetics that ABCA7 plays a greater role in AD pathogenesis in European ancestry individuals and lay a foundation for further studies of the mechanisms that underlie ancestral difference in the ABCA7 effect on AD.

抽象的种族和文化多样性可以带来经济和社会效益。这也给治疗带来了挑战发展和卫生保健的提供。然而，血统并没有得到一致的考虑直到最近，精准医疗的需求变得显而易见。因此缺乏相关研究疾病病理学的祖先差异，甚至是研究这些疾病的既定方法的差异差异。小鼠模型似乎不适合通过血统进行病理生理学研究。目的本研究的目的是阐明三磷酸腺苷结合盒转运蛋白亚家族 A 损失了多少成员 7 (ABCA7) 影响欧洲、非洲和东亚个体的淀粉样蛋白 β (Aβ) 代谢使用人类诱导多能干（iPS）细胞衍生的神经元进行血统研究。 ABCA7 被认为是阿尔茨海默病 (AD) 病理学中许多基因组关联和基因组测序的危险因素研究欧洲、非洲以及较小程度上的东亚血统。在初步数据中，我们确认遗传学观察表明，在大约 145 名 AD 受试者和对照组受试者的队列中，大多数受试者欧洲血统的 ABCA7 水平极低的个体表现出 AD 发病加速。我们也表明使用 CRISPR/Cas9 在来自欧洲个体的 iPS 细胞衍生的神经元中删除 ABCA7 血统导致 Aβ 分泌增加。最后，我们确认 ABCA7 功能丧失等位基因是通过检查来自非洲血统的全外显子组测序数据，发现这种现象在非洲血统中很常见（~5％的次要等位基因频率）生物库中来自费城的一群人。人类遗传学研究发现，功能丧失欧洲血统人群中 ABCA7 的等位基因使 AD 风险增加数倍，而 ABCA7 非洲血统人群中的功能丧失等位基因最多可增加 80% 的患病风险。基于此，我们提出这样的假设：非洲血统中 ABCA7 的缺失比非洲血统中的损失要小。欧洲血统。为了检验这一假设，我们建议删除以下个体 iPS 细胞中的 ABCA7：非洲和东亚血统，并确定该基因的丢失对 iPS 细胞中 Aβ 合成的影响程度这两个祖先的衍生神经元与欧洲祖先的 iPS 细胞衍生的神经元进行了比较。根据遗传学研究，预测来自受试者的 iPS 细胞来源的神经元中 ABCA7 缺失非洲血统提高 Aβ 产量的水平低于欧洲血统 iPS 细胞衍生的神经元科目。拟议的工作将展示 iPS 细胞衍生的神经元是否可用于研究祖先的病理生理学差异符合人类遗传学的观察结果，ABCA7 发挥着在欧洲血统个体的 AD 发病机制中发挥更大的作用，并为进一步研究奠定基础 ABCA7 对 AD 影响的祖先差异背后的机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Alzheimer's disease GWAS risk alleles in the ABCA7 promoter and 5' region reduce ABCA7 expression.

DOI：
10.1007/s00401-022-02459-8
发表时间：
2022-09
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
通讯作者：

Specificity of ABCA7-mediated cell lipid efflux.

DOI：
10.1016/j.bbalip.2022.159157
发表时间：
2022-07
期刊：
Biochimica et biophysica acta. Molecular and cell biology of lipids
影响因子：
0
作者：
通讯作者：

Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA.

DOI：
10.3390/cells12172143
发表时间：
2023-08-25
期刊：
CELLS
影响因子：
6
作者：
Wiener, Joel P.;Desire, Sindy;Garliyev, Viktor;Lyssenko III, Nicholas;Pratico, Domenico;Lyssenko, Nicholas N.
通讯作者：
Lyssenko, Nicholas N.