Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer’s disease risk

International Journal of Molecular Epidemiology and Genetics

Scott Miners¹  Patrick G Kehoe¹  Peter A Passmore¹  Stephen Todd¹  Bernadette M McGuinness¹  Jonathan A Prince¹  Rachel Barker¹  Davide Seripa¹  Zoë van Helmond¹  Seth Love¹  Francesco Panza¹  Janet A Johnston¹  Vincenzo Solfrizzi¹ 

关键词: Neprilysin;    MME;    gene;    association;    β-Amyloid;    alzheimer disease;    polymorphism;   

DOI  :  

学科分类：流行病学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

Unknown