Medical Genetics, Molecular Medicine Centre, University of Edinburgh, Edinburgh, UK.
Am J Med Genet B Neuropsychiatr Genet. 2012 Sep;159B(6):696-709. doi: 10.1002/ajmg.b.32073. Epub 2012 Jun 12.
The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z < 0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE ε4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.
β-淀粉样肽可能在阿尔茨海默病（AD）发病机制中起核心作用。我们评估了七个 Aβ 降解基因（ACE、ECE1、ECE2、IDE、MME、PLAU 和 TF）中的变体与遗传和环境风险在阿尔茨海默病协会 1（GERAD1）队列中的 AD 风险之间的关联，以及与三个认知表型之间的关联在洛锡安出生队列 1936（LBC1936）中，分别使用 128 和 121 个 SNP。在 GERAD1 中，我们发现一个四个 SNP 内的 ECE1 单倍型与携带至少一个 APOE ε4 等位基因的个体的 AD 风险之间存在显著关联（P = 0.00035，优势比 = 1.61）。在 LBC1936 中，我们发现一个不同的两个 SNP 内的 ECE1 单倍型与缺乏 APOE ε4 等位基因的个体的非言语推理之间存在显著关联（P = 0.00036，β = -0.19）。经过置换后，这两个结果都显示出显著的趋势（0.05 < P < 0.10）。一项后续的认知遗传研究评估了三个无痴呆老年人队列中 ECE1 SNP 的关联。四个队列的荟萃分析确定了 ECE1b 启动子中的 SNP 与非言语推理评分之间的显著关联（Z < 0.05），特别是在缺乏 APOE ε4 等位基因的个体中。我们的遗传发现并不完全一致。尽管如此，与 AD 相关的内含子单倍型与已知的 ECE1b 启动子变体 338A 的变体 338C > A（rs213045）相关。我们在两个人类神经母细胞瘤细胞系中观察到 338A 变体的表达明显减少，并推测该启动子可能受到组织特异性调节。
