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Neurology DOI:10.1212/WNL.0b013e3182452b40

Genetic variation at CR1 increases risk of cerebral amyloid angiopathy.

Publication TypeJournal Article
Year of Publication2012
AuthorsBiffi, A, Shulman, JM, Jagiella, JM, Cortellini, L, Ayres, AM, Schwab, K, Brown, DL, Silliman, SL, Selim, M, Worrall, BB, Meschia, JF, Slowik, A, De Jager, PL, Greenberg, SM, Schneider, JA, Bennett, DA, Rosand, J
Date Published2012 Jan 31
KeywordsAge Factors, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Autopsy, Cerebral Amyloid Angiopathy, Confidence Intervals, Data Interpretation, Statistical, Female, Follow-Up Studies, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Kaplan-Meier Estimate, Longitudinal Studies, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Complement 3b, Risk, Sex Factors

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 ICH-free 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.


Alternate JournalNeurology
PubMed ID22262751
PubMed Central IDPMC3280047
Grant ListR01 AG026484 / AG / NIA NIH HHS / United States
UL1 TR000064 / TR / NCATS NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
P30-AG10161 / AG / NIA NIH HHS / United States
R01-AG15819 / AG / NIA NIH HHS / United States
R01-AG30146 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01-NS059727 / NS / NINDS NIH HHS / United States
R01-AG179917 / AG / NIA NIH HHS / United States
K08-AG0344290 / AG / NIA NIH HHS / United States
R01 NS063925 / NS / NINDS NIH HHS / United States
M01-RR000042 / RR / NCRR NIH HHS / United States
P50-NS051343 / NS / NINDS NIH HHS / United States
R01-NS063925 / NS / NINDS NIH HHS / United States
K23-NS064052 / NS / NINDS NIH HHS / United States
R01-AG026484 / AG / NIA NIH HHS / United States
K23-NS059774 / NS / NINDS NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States