@article{9a65b6116f414b8ea6d57da6889794fe,
title = "Genetic variation at CR1 increases risk of cerebral amyloid angiopathy",
abstract = "Objective: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences β-amyloid (Aβ) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aβ deposition. Methods: We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICHfree control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. Results: rs6656401 was associated with CAA-ICH (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19-2.17, p = 8.0 × 10-4) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04-1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA. Conclusion: The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.",
author = "A. Biffi and Shulman, {J. M.} and Jagiella, {J. M.} and L. Cortellini and Ayres, {A. M.} and K. Schwab and Brown, {D. L.} and Silliman, {S. L.} and M. Selim and Worrall, {B. B.} and Meschia, {J. F.} and A. Slowik and {De Jager}, {P. L.} and Greenberg, {S. M.} and Schneider, {J. A.} and Bennett, {D. A.} and J. Rosand",
note = "Funding Information: The GOCHA study was supported by the Edward and Maybeth Sonn Research Fund, the University of Michigan General Clinical Research Center (M01-RR000042) , the National Institute for Neurologic Disorders and Stroke (R01-NS063925, R01-NS059727, P50-NS051343, K23-NS064052, and K23-NS059774) and the National Institute on Aging (R01-AG026484) . Dr. Biffi received support from the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775011N, 0755984T) . The ROS and MAP studies are supported by NIH grants (R01-AG30146, R01-AG179917, R01-AG15819, P30-AG10161, and K08-AG0344290) . Funding Information: Dr. Biffi receives research support from the American Heart Association Bugher Foundation. Dr. Shulman receives research support from the NIH/NIA, 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, Inc., Parkinson's Study Group, Harvard NeuroDiscovery Center/Massachusetts Alzheimer's Disease Research Center, and Burroughs Wellcome Fund, Career Award for Medical Scientists. Dr. Jagiella reports no disclosures. L. Cortellini receives research support from the NIH/NINDS. A.M. Ayres receives research support from the NIH. K. Schwab receives research support from the NIH (NINDS, NIA). Dr. Brown serves on the editorial board of Neurology {\textregistered}; is supported by an NINDS Career Development Award (K23 NS051202) ; and has received research support from CVR Global, Inc., the University of Michigan, Michigan Department of Community Health, Blue Cross Blue Shield of Michigan Foundation, the Diocese of Corpus Christi, and the NIH. Dr. Brown has received speaker honoraria from the Hazel K. Goddess Fund for Stroke Research in Women and receives research support from the NIH (NINDS, NHLBI). Dr. Silliman serves on the speakers' bureau for and has received speaker honoraria from Biogen Idec and has received research support from Biogen Idec, Novartis, Genzyme Corporation, Schering-Plough Corp., and the NIH/NINDS. Dr. Selim serves on scientific advisory boards for Mitsubishi Tanabe Pharma Corporation and Avanir Pharmaceuticals; serves as Controversies Section Co-editor for Stroke ; receives publishing royalties for The Stroke Book (Cambridge University Press, 2007) and Neurology Emergencies (Oxford University Press, 2011); and receives research support from the NIH. Dr. Worrall serves as an Associate Editor of Neurology {\textregistered} and on the editorial board of Seminars in Neurology ; receives royalties from the publication of Merritt's Neurology, 10th, 11th, and 12th eds. (chapter author); and receives/has received research support from the NIH (NHGRI, NHLBI, NINDS) and from the University of Virginia–CTSA Pilot Project. Dr. Meschia serves on the editorial boards of Stroke and the Journal of Stroke and Cerebrovascular Diseases and receives research support from the NIH/NINDS. Dr. Slowik reports no disclosures Dr. De Jager has served on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Biogen Idec; has received speaker honoraria from Biogen Idec; serves on the editorial board of Journal of Neuroimmunology ; and receives research support from Biogen Idec and the NIH. Dr. Greenberg serves on a data safety monitoring board for the NIH/NINDS; has received speaker honoraria from Esteve, Medtronics, Inc., and Pfizer Inc; serves on the editorial boards of Neurology {\textregistered}, Stroke, Cerebrovascular Disease , and the Journal of Alzheimer's Disease and Other Dementias ; has served as a consultant for Roche, Janssen Alzheimer Immunotherapy, and Bristol-Myers Squibb; and has received/receives research support from the NIH and the Alzheimer's Association. Dr. Schneider served on a scientific advisory board for GE Healthcare; serves as Monitoring Editor for the Journal Histochemistry and Cytochemistry , on the editorial board of the International Journal of Clinical and Experimental Pathology , and as Associate Editor for the Journal of Alzheimer's Disease ; serves as a consultant for Avid Radiopharmaceuticals, Inc.; and receives research support from Avid Radiopharmaceuticals, Inc. and the NIH. Dr. Bennett serves on the editorial boards of Neurology {\textregistered}, Neuroepidemiology , and Current Alzheimer's Research ; serves on the scientific advisory board for Vigorous Minds; serves/has served as a consultant to Schering-Plough Corp., Double Helix Development, Medivation, Inc., Danone Research B.V., and Gerson Lehrman Group; and receives research support from Danone Research B.V., the NIH, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. Dr. Rosand receives research support from the NIH (NINDS, NHLBI), the American Heart Association–Bugher Foundation, and the MGH Deane Institute for Integrative Research in Atrial Fibrillation and Stroke. ",
year = "2012",
month = jan,
day = "31",
doi = "10.1212/WNL.0b013e3182452b40",
language = "English (US)",
volume = "78",
pages = "334--341",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "5",
}