Genetic variation at CR1 increases risk of cerebral amyloid angiopathy
Genetic variation at CR1 increases risk of cerebral amyloid angiopathy
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DOI：
10.1212/wnl.0b013e3182452b40
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发表时间：
2012-01-01
期刊：
影响因子：
9.9
通讯作者：
Rosand, J.
中科院分区：
文献类型：
--
作者：
Biffi, A.;Shulman, J. M.;Rosand, J.
目的：积累的证据表明，已知会增加阿尔茨海默病 (AD) 风险的 CR1 基因内的变异（单核苷酸多态性 rs6656401）会影响脑组织中的 β-淀粉样蛋白 (Aβ) 沉积。鉴于 AD 和脑淀粉样血管病 (CAA) 之间的生物学重叠，脑淀粉样血管病 (CAA) 是老年人脑出血 (ICH) 的主要原因，我们研究了 rs6656401 是否会增加 CAA 相关 ICH 的风险并影响血管 Aβ 沉积。方法：我们对 89 名 CAA 相关 ICH 个体和 280 名与 CAA 无关的 ICH 个体进行了病例对照遗传关联研究，并将其与 324 名 ICH 个体进行比较。 ICHfree 对照受试者。我们还研究了 rs6656401 对 ICH 幸存者前瞻性纵向队列中 CAA-ICH 复发风险的影响。最后，在来自 2 项衰老纵向研究的 544 份尸检标本中研究了与组织病理学 CAA 严重程度的关联。结果：rs6656401 与 CAA-ICH 相关（比值比 [OR] = 1.61，95% 置信区间 [CI] 1.19-2.17，p = 8.0 x 10(-4)）以及复发 CAA-ICH 的风险（风险比 = 1.35，95% CI 1.04-1.76，p = 0.024）。 rs6656401 的基因型还与尸检时 CAA 病理的严重程度相关（OR = 1.34，95% CI 1.05-1.71，rho = 0.009）。对实质淀粉样蛋白负荷的调整并没有消除这种效应，这表明，尽管实质和血管淀粉样蛋白病理学之间存在相关性，但CR1对这两个过程独立起作用，从而增加了AD和CAA的风险。结论：CR1变体rs6656401影响CAA-ICH的风险和复发，以及血管淀粉样蛋白沉积的严重程度。神经病学（R）2012；78：334-341
Objective: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences beta-amyloid (A beta) 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 A beta deposition.Methods: We performed a case-control genetic association study of 89 individuals with CAArelated 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 x 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, rho = 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. Neurology (R) 2012;78:334-341