Variants of CYP46A1 may interact with age and APOE to influence CSF Aβ42 levels in Alzheimer's disease
Variants of CYP46A1 may interact with age and APOE to influence CSF Aβ42 levels in Alzheimer's disease
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DOI：
10.1007/s00439-004-1107-9
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发表时间：
2004-05-01
期刊：
影响因子：
5.3
通讯作者：
Prince, JA
中科院分区：
文献类型：
--
作者：
Johansson, A;Katzov, H;Prince, JA
最近的研究表明，编码胆固醇24-羟化酶（CYP46）的CYP46A1变异会增加阿尔茨海默病（AD）的风险，这一前景得到了与AD病理相关的几个数量性状的遗传关联证据的证实，包括脑脊液（CSF）中β -淀粉样蛋白（Abeta42）和tau蛋白42个氨基酸切割产物的水平。在目前的研究中，通过在三个独立的北欧病例对照系列中对CYP46A1先前相关标记物进行基因分型，包括1323名个体，包括大约400名患者，测量CSF Abeta42和磷酸化tau蛋白水平，对这些说法进行了探索。在病例对照模型中的关联测试显示，有限的证据表明CYP46A1变异对这些样本中的AD风险有贡献。然而，测试对CSF测量的潜在影响的模型表明，内含子标记（rs754203）可能与年龄和APOE基因型相互作用。在分层分析中，脑脊液Abeta42 （P=0.0009）和phospho-tau （P=0.046）的显著影响仅限于老年APOE epsilon4携带者。计算分析表明，rs754203标记可能不会影响调节因子的结合，这表明其他多态性位点可能是观察到的关联的基础。我们的研究结果为之前的发现提供了重要的独立复制，支持CYP46A1序列变异的存在，该变异有助于β -淀粉样蛋白代谢的变异性。
Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), confer risk for Alzheimer's disease (AD), a prospect substantiated by evidence of genetic association from several quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of beta-amyloid (Abeta42) and the tau protein. In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent northern European case-control series encompassing 1323 individuals and including approximately 400 patients with measurements of CSF Abeta42 and phospho-tau protein levels. Tests of association in case-control models revealed limited evidence that CYP46A1 variants contributed to AD risk across these samples. However, models testing for potential effects upon CSF measures suggested a possible interaction of an intronic marker (rs754203) with age and APOE genotype. In stratified analyses, significant effects were evident that were restricted to elderly APOE epsilon4 carriers for both CSF Abeta42 (P=0.0009) and phospho-tau (P=0.046). Computational analyses indicate that the rs754203 marker probably does not impact the binding of regulatory factors, suggesting that other polymorphic sites underlie the observed associations. Our results provide an important independent replication of previous findings, supporting the existence of CYP46A1 sequence variants that contribute to variability in beta-amyloid metabolism.