Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.
PLoS One. 2010 Jan 19;5(1):e8764. doi: 10.1371/journal.pone.0008764.
The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).
METHODOLOGY/PRINCIPAL FINDINGS: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association.
Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.
胰岛素降解酶基因（IDE）是晚发性阿尔茨海默病（LOAD）的一个强有力的功能和位置候选基因。
方法/主要发现：我们在 269 例 AD 病例和 252 例对照中检查了 IDE 及其 10 kb 侧翼的保守区域，从而鉴定了 17 个假定的功能性多态性。这些变体形成了 11 个单倍型，其中 10 个变体被标记。其中四个变体在来自 194 例 LOAD 小脑的样本中显示出与 IDE 转录水平的显著关联。最强的 rs6583817 以前没有报道过，显示出明确的关联（p = 1.5x10(-8)，倍数增加= 2.12）；这 11 个单倍型也与转录水平显著相关（全局 p = 0.003）。使用体外双荧光素酶报告基因检测，我们发现 rs6583817 增加了 Be(2)-C（p = 0.006）和 HepG2（p = 0.02）细胞系中报告基因的表达。此外，使用最近对两个克罗地亚孤立人群进行的全基因组关联研究的数据（n = 1,879），我们鉴定了一个与 rs6583817 显著相关的代表物，该代表物与降低血浆 Abeta40 水平（ss = -0.124，p = 0.011）和总测量的血浆 Abeta 水平（b = -0.130，p = 0.009）显著相关。最后，rs6583817 与 3,891 例 AD 病例和 3,605 例对照中的 LOAD 风险降低相关（OR = 0.87，p = 0.03），11 个 IDE 单倍型（全局 p = 0.02）也显示出显著的关联。
因此，与 IDE 表达增加明确相关的以前未报道的变体也与降低的血浆 Abeta40 和降低的 LOAD 易感性相关。LOAD 和 IDE 之间的遗传关联一直难以复制。我们的研究结果表明，针对与尸检脑组织样本中改变的转录水平强烈相关的表达单核苷酸多态性（eSNP）的靶向测试可能是一种强有力的方法，可以识别 LOAD 的遗传关联，否则这些关联很难检测到。
