Alpha-2 macroglobulin is genetically associated with Alzheimer disease
Alpha-2 macroglobulin is genetically associated with Alzheimer disease
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DOI：
10.1038/1243
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发表时间：
1998-08-01
期刊：
影响因子：
30.8
通讯作者：
Tanzi, RE
中科院分区：
文献类型：
--
作者：
Blacker, D;Wilcox, MA;Tanzi, RE
α-2-巨球蛋白（α-M-2;由基因A2 M编码）是一种血清泛蛋白酶抑制剂，基于其介导A β（β-淀粉样蛋白沉积物的主要成分）清除和降解的能力，其与阿尔茨海默病（AD）有关。对诱饵区（外显子18）“外显子II "5'剪接位点处A2 M基因缺失的分析显示，缺失（A2 M-2）的遗传增加了AD的风险（Mantel-Haenzel比值比=3.56，P=0.001）。同胞关系不平衡检验（SDT）也显示A2 M与AD之间存在显著关联（P=0.00009）。这些值与同一样本中APOE-E14等位基因获得的值相当，但与APOE-E14相反。A2 M-2不影响发病年龄。观察到的A2 M与AD的关联似乎不能解释先前发表的AD与12号染色体的连锁，我们无法在该样本中证实。A2 M、LRP 1（编码α-M-2受体）和另外两种LRP配体的基因，APOE和APP（编码淀粉样P蛋白前体），现在都与AD遗传相关，表明这些蛋白质可能参与导致AD的共同神经致病途径。
Alpha-2-macroglobulin (alpha-M-2; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon 4 allele in the same sample, but in contrast to APOE-epsilon 4. A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-M-2 receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid P-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.