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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.

摘要种族和文化多样性带来经济和社会效益。它也对治疗性疾病提出了挑战。发展和提供保健。然而，祖先并没有得到一贯的考虑直到最近，对精准医疗的需求变得明显。因此，缺乏研究，疾病病理学的祖先差异，甚至是关于如何研究这种疾病的成熟方法，差异小鼠模型似乎不适合研究祖先的病理生理学。目的本研究的目的是阐明腺苷三磷酸结合盒转运子亚家族A ABCA 7影响欧洲、非洲和东亚个体的淀粉样蛋白β（Aβ）代谢使用人诱导多能干（iPS）细胞衍生的神经元的祖先。ABCA 7被认为是阿尔茨海默病（AD）病理学中的危险因素在许多全基因组关联和基因组测序中研究欧洲，非洲，在较小程度上，东亚血统。根据初步数据，我们确认从遗传学的观察，并显示，在一个队列的约145 AD和对照组的主要欧洲血统，ABCA 7水平非常低的个体表现出加速的AD发病机制。我们也显示在来自欧洲人个体iPS细胞衍生的神经元中使用CRISPR/Cas9缺失ABCA 7 祖先导致Aβ分泌增加。最后，我们证实ABCA 7功能缺失等位基因是常见的（~5%的次要等位基因频率）在非洲血统，通过检查全外显子组测序数据，从一个来自费城的一群人人类遗传学研究发现，欧洲血统人群中ABCA 7的等位基因使AD的风险增加数倍，而ABCA 7 非洲血统人群中的功能丧失等位基因使该疾病的风险最多增加80%。基于此，我们提出了这样的假设，即非洲血统中ABCA 7的缺失比非洲血统中ABCA 7的缺失危害更小。欧洲血统。为了验证这一假设，我们建议删除来自以下个体的iPS细胞中的ABCA 7：非洲和东亚血统，并确定该基因的缺失对iPS细胞中Aβ合成的影响程度- 这两个祖先的iPS细胞衍生的神经元与欧洲祖先的iPS细胞衍生的神经元相比。基于遗传学研究，预测来自受试者的iPS细胞衍生的神经元中ABCA 7的缺失是可能的。非洲血统将比来自欧洲血统的iPS细胞衍生的神经元更少地提高Aβ的产生科目这项工作将显示iPS细胞衍生的神经元是否可以用于研究根据祖先的病理生理差异，符合人类遗传学的观察结果，ABCA 7起着重要的作用。在AD发病机制中发挥更大的作用，并为进一步研究AD发病机制奠定基础。 ABCA 7对AD的作用的祖先差异的基础机制。

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.