Liao A, Nitsch R M, Greenberg S M, Finckh U, Blacker D, Albert M, Rebeck G W, Gomez-Isla T, Clatworthy A, Binetti G, Hock C, Mueller-Thomsen T, Mann U, Zuchowski K, Beisiegel U, Staehelin H, Growdon J H, Tanzi R E, Hyman B T
Alzheimer Research Unit, Neurology Service, Massachusetts General Hospital, 149 13th Street (CNY 6405), Charlestown, MA 02129, USA.
Hum Mol Genet. 1998 Nov;7(12):1953-6. doi: 10.1093/hmg/7.12.1953.
alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.
α2-巨球蛋白（A2M）是一种蛋白酶抑制剂，在阿尔茨海默病（AD）中与老年斑（SP）相关。在生化方面，A2M参与了在SP中积累的淀粉样β蛋白（Aβ）的结合和降解。我们研究了阿尔茨海默病与一种常见的A2M多态性Val1000（GTC）/Ile1000（ATC）之间的关系，该多态性位于分子的硫酯活性位点附近。在一个初始探索性数据集（90名对照和171名阿尔茨海默病患者）中，我们注意到G/G基因型的频率从0.07增加到了0.12。因此，我们在另一个独立数据集中检验了G/G基因型在阿尔茨海默病中过度表达的假设：一组359名对照和566名阿尔茨海默病患者。在假设检验队列中，G/G基因型从对照中的0.07增加到阿尔茨海默病患者中的0.12（P<0.05，Fisher精确检验）。与G/G基因型相关的阿尔茨海默病的优势比为1.77（1.16 - 2.70，P<0.01），与APOE4联合时为9.968（95%可信区间3.91 - 24.0，P<0.001）。在一个小样本系列中，G等位基因的存在与Aβ负荷增加相关。A2M受体A2M-r/LRP是一种多功能受体，其配体包括载脂蛋白E和淀粉样前体蛋白。这四种蛋白质在基因上均与阿尔茨海默病相关，表明它们可能参与了共同的疾病途径。
