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首页> 外文期刊>Translational Stroke Research >TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease
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TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease

机译：脑淀粉样血管病相关脑出血中的TOMM40：与阿尔茨海默氏病的比较遗传分析

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摘要

Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer’s disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p < 0.05 after multiple testing correction), but not CAA-related ICH (all p > 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p < 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p < 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.
机译：脑淀粉样血管病（CAA）相关的脑内出血（ICH）是中风的毁灭性形式，尚无已知疗法。临床，神经病理学和遗传学研究表明，CAA的发病机理与阿尔茨海默氏病（AD）的生物学相关疾病之间既有重叠也有分歧。与AD相关的遗传基因座中有APOE和TOMM40，这是一个与APOE非常接近的基因。我们在这里调查TOMM40内的变异是否与CAA相关的ICH和CAA神经病理学相关。利用麻省总医院（MGH）和阿尔茨海默氏病神经影像学计划（ADNI）的队列，我们​​设计了CAA相关性ICH和AD的高密度SNP基因型数据的比较分析。 APOEε4与CAA相关的ICH和AD相关，而APOEε2在AD中具有保护作用，但是CAA的危险因素。 TOMM40内共有14个SNP与AD相关（多次测试校正后p <0.05），但与CAA相关的ICH不相关（所有p> 0.20）；结果，TOMM40中所有与AD相关的SNP在CAA相关的ICH中显示出异质性（BD p <0.001）。然而，在宗教秩序研究（ROS）和仓促记忆与衰老计划（MAP）中对CAA神经病理学的分析发现，神经炎性斑块，弥散性斑块负担和血管淀粉样蛋白负担与所有TOMM40 SNP相关（p <0.02）。这些结果表明，TOMM40的改变可以促进血管以及斑块淀粉样蛋白的沉积，但不能促进导致CAA相关性ICH的全部致病途径。

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  • 来源
    《Translational Stroke Research》 |2012年第s1期|102-112|共11页
  • 作者

    Valerie Valant; Brendan T. Keenan; Christopher D. Anderson; Joshua M. Shulman; William J. Devan; Alison M. Ayres; Kristin Schwab; Joshua N. Goldstein; Anand Viswanathan; Steven M. Greenberg; David A. Bennett; Philip L. De Jager; Jonathan Rosand; Alessandro Biffi;

  • 作者单位

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

    Program in Medical and Population Genetics Broad Institute Cambridge MA USA;

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

    Program in Medical and Population Genetics Broad Institute Cambridge MA USA;

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

    Hemorrhagic Stroke Research Group Massachusetts General Hospital Boston MA USA;

    Hemorrhagic Stroke Research Group Massachusetts General Hospital Boston MA USA;

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

    Hemorrhagic Stroke Research Group Massachusetts General Hospital Boston MA USA;

    Hemorrhagic Stroke Research Group Massachusetts General Hospital Boston MA USA;

    Rush Alzheimer’s Disease Center Department of Neurological Science Rush University medical Center Chicago IL USA;

    Program in Medical and Population Genetics Broad Institute Cambridge MA USA;

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

    Division of Neurocritical Care and Emergency Neurology Department of Neurology Massachusetts General Hospital Boston MA USA;

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  • 正文语种 eng
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  • 关键词

    TOMM40; APOE; Cerebral amyloid angiopathy; Alzheimer’s disease; Linkage disequilibrium;

    机译：TOMM40;APOE;脑淀粉样血管病;阿尔茨海默氏病;连锁不平衡;

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