Miners Scott, van Helmond Zoë, Barker Rachel, Passmore Peter A, Johnston Janet A, Todd Stephen, McGuinness Bernadette M, Panza Francesco, Seripa Davide, Solfrizzi Vincenzo, Love Seth, Prince Jonathan A, Kehoe Patrick G
Dementia Research Group, University of Bristol, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.
Int J Mol Epidemiol Genet. 2012;3(1):30-8. Epub 2012 Feb 5.
Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ(1-42), and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.
中性内肽酶（NEP），也被称为膜金属内肽酶（MME），被认为是预防阿尔茨海默病（AD）病理过程中最重要的β-淀粉样蛋白（Aβ）降解酶之一。NEP基因（MME）的变异已被认为是AD的一个风险因素。我们在一个由1057例可能和确诊的AD病例以及来自英国、意大利和瑞典的424例年龄匹配的非痴呆对照组成的队列中，对7个MME单核苷酸多态性（SNP）——rs1836914、rs989692、rs9827586、rs6797911、rs61760379、rs3736187、rs701109——与AD风险进行了基因关联研究。我们还在一组有死后脑组织的AD和对照病例中，研究了这些MME SNP与NEP蛋白水平和酶活性以及额叶皮质中Aβ积累的生化指标——总可溶性Aβ、寡聚Aβ（1-42）和胍提取物（不溶性）Aβ水平——之间的关联。在多变量逻辑回归分析中，其中一个MME变异（rs6797911）与AD风险相关（P = 0.00052，比值比（O.R.） = 1.40，95%置信区间（1.16 - 1.70））。没有一个SNP与Aβ水平有任何关联；然而，rs9827586与NEP蛋白水平（p = 0.014）和酶活性（p = 0.006）显著相关。rs701109与NEP蛋白水平之间也发现了关联（p = 0.026），rs989692存在边缘性非显著关联（p = 0.055）。这些数据表明MME变异可能与AD风险相关，但我们尚未找到证据表明这是通过改变NEP蛋白水平或活性介导的。
