Department of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
J Alzheimers Dis. 2011;24(3):587-97. doi: 10.3233/JAD-2011-101914.
A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.
阿尔茨海默病（AD）的一个关键病理特征是淀粉样β（Aβ）肽的异常细胞外积累。因此，Aβ 降解的改变可能是导致 LOAD 发展的主要原因。编码 Aβ 降解酶血管紧张素转化酶（ACE）的基因中的变异因此代表与 LOAD 病理和风险相关的合理候选者。在对所有已发表的病例对照研究进行 Alzgene 荟萃分析后，ACE 变体 rs4291 和 rs1800764 与 LOAD 风险显著相关。此外，ACE 单倍型与血浆 ACE 水平和 LOAD 风险相关。我们在十个高加索病例对照人群（n = 8212）中测试了三个 ACE 变体（rs4291、rs4343 和 rs1800764）与 LOAD 的关联。使用多元逻辑模型未发现关联（所有 p > 0.09）。我们发现没有群体异质性（所有 p > 0.38），也没有证据表明在对 rs4343（OR = 1.00）、rs4291（OR = 0.97）或 rs1800764（OR = 0.99）的十个群体进行荟萃分析后与 LOAD 风险相关。尽管我们在完整的数据集（p = 0.51）中没有发现单倍型关联，但在一个群体中观察到一个显著的全局单倍型 p 值（p = 0.007），这是由于 H3 单倍型的关联（OR = 0.72，p = 0.02）和 H4 的关联趋势（OR = 1.38，p = 0.09）和 H7（OR = 2.07，p = 0.08），尽管这些在经过 Bonferroni 校正后没有幸存下来。ACE 变体与 LOAD 的先前关联将在这项研究之后减弱。ACE 变体的最佳效果是具有适度的效果大小，这可能是遗传、表型和药理学效应之间复杂相互作用的一部分，而在传统的病例对照研究中则无法检测到。
