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TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease

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Abstract

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.

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Acknowledgement

The authors thank the participants at MGH and within the ROS and the MAP, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Rush Alzheimer’s Disease Center, and the Broad Institute.

Financial Disclosure

The authors declare that they have no conflict of interest.

Funding/Support

This work was supported by the John and Marilyn Keane Stroke Genetics Fund, the Edward and Maybeth Sonn Research Fund, NINDS R01NS059727, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Institutes for Health (NIH) (grant U01 AG024904). The ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott Laboratories, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation Plc, Genentech Inc, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson Services Inc, Eli Lilly and Company, Medpace Inc, Merck and Co Inc, Novartis International AG, Pfizer Inc, F. Hoffman-La Roche Ltd, and Wyeth Pharmaceuticals, as well as nonprofit partners the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to the ADNI are facilitated by the Foundation for the NIH. The grantee organization is the Northern California Institute for Research and Education Inc, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angles. This research was also supported by the NIH (grants P30 AG010129 and K01 AG030514) and the Dana Foundation. Drs Biffi and Anderson receive research support from the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (grant 0775010 N). Dr. Shulman is supported by the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center and Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer Inc. and Merck & Co., Parkinson’s Study Group, Harvard NeuroDiscovery Center/Massachusetts Alzheimer’s Disease Research Center, and Burroughs Wellcome Fund, Career Award for Medical Scientists. Dr Bennett receives research support from Danone Research B.V., the NIH, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. Dr DeJager receives research support from Biogen Idec and the NIH. Dr Rosand receives research support from the National Center for Research Resources. Dr Goldstein (grant K23NS059774) receives research support from the National Institute of Health-National Institute of Neurological Disorders and Stroke.

Additional Contributions

We would like to thank Tammy Gills, PhD, and Marcy MacDonald, PhD, for technical assistance in genotyping APOE variants and the investigators participating in the ADNI study, who contributed to the design and implementation of the ADNI and/or provided data but did participate in the analysis or writing of this report.

Author Contributions

Study concept and design: Valant, Rosand and Biffi. Acquisition of data: Valant, Shulman, Devan, Ayres, Schwab, Goldstein, Viswanathan, Greenberg, Bennett, DeJager, Rosand and Biffi. Analysis and interpretation of data: Valant, Keenan, Anderson, Devan, Rosand and Biffi. Drafting of the manuscript: Valant and Biffi. Critical revision of the manuscript for important intellectual comment: Valant, Keenan, Anderson, Shulman, Devan, Ayres, Schwab, Goldstein, Viswanathan, Greenberg, Bennett, De Jager, Rosand and Biffi. Statistical analysis: Keenan, Shulman, Devan and Biffi. Obtained funding: Goldstein, Greenberg, Bennett, De Jager and Rosand. Administrative, technical, and material support: Valant, Ayres and Schwab. Study supervision: Bennett, De Jager, Rosand and Biffi.

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Authors and Affiliations

  1. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Valerie Valant, Christopher D. Anderson, William J. Devan, Joshua N. Goldstein, Jonathan Rosand & Alessandro Biffi

  2. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, CPZN 6818, Boston, MA, 02114, USA

    Valerie Valant, Christopher D. Anderson, William J. Devan, Jonathan Rosand & Alessandro Biffi

  3. Hemorrhagic Stroke Research Group, Massachusetts General Hospital, Boston, MA, USA

    Valerie Valant, Christopher D. Anderson, William J. Devan, Alison M. Ayres, Kristin Schwab, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Jonathan Rosand & Alessandro Biffi

  4. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    Valerie Valant, Brendan T. Keenan, Christopher D. Anderson, Joshua M. Shulman, William J. Devan, Philip L. De Jager, Jonathan Rosand & Alessandro Biffi

  5. Program in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Brendan T. Keenan, Joshua M. Shulman & Philip L. De Jager

  6. Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

    Joshua N. Goldstein

  7. Rush Alzheimer’s Disease Center, Department of Neurological Science, Rush University medical Center, Chicago, IL, USA

    David A. Bennett

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  1. Valerie Valant
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the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

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Correspondence to Jonathan Rosand.

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Valant, V., Keenan, B.T., Anderson, C.D. et al. TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease. Transl. Stroke Res. 3 (Suppl 1), 102–112 (2012). https://doi.org/10.1007/s12975-012-0161-1

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