APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.
APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.
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发表时间：
1995
期刊：
影响因子：
30.8
通讯作者：
M. Kamboh;D. Sanghera;R. Ferrell;S. DeKosky
中科院分区：
文献类型：
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作者：
M. Kamboh;D. Sanghera;R. Ferrell;S. DeKosky
阿尔茨海默病（Alzheimer's disease， AD）是一种毁灭性的神经退行性疾病，基因研究发现载脂蛋白E （APOE）基因是AD的一个强易感性标记。无论发病年龄或家族史如何，APOE的E*4等位基因都是AD的主要危险因素。然而，APOE*4等位基因既不是AD表达的必要条件，也不是充分条件，这一观察结果强调了其他环境或遗传因素的参与，无论是与APOE*4共同作用还是单独作用，都会增加个体患AD的风险。在可能影响这种多因子疾病风险的候选基因中，编码α - 1抗凝乳胰蛋白酶（ACT）的基因。与APOE蛋白一样，ACT在AD脑的丝状沉积物中以高亲和力结合β -淀粉样肽（A β P），并作为A β P聚合成淀粉样丝状物的强烈刺激因子。在AD大脑中，ACT表达增强，特别是在发生淀粉样斑块的区域，这表明ACT可能在AD的发病机制中发挥重要作用。本研究表明，ACT信号肽的常见多态性与AD的发病风险有关。此外，与AD风险相关的APOE*4基因剂量效应被ACT多态性显著改变。我们还确定了ACT/AA和APOE 4/4基因型的独特组合作为AD的潜在易感性标记，因为其频率在AD组中为1/17，而在普通人群对照组中为1/313。我们的数据表明，ACT作为一个修饰基因，改变了传统上与APOE*4等位基因相关的AD风险。
Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.