The Association of MME microRNA Binding Site Polymorphism with the Risk of Late Onset Alzheimer's Disease in Northern Han Chinese

Background: Although β-amyloid (Aβ) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aβ degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs). Objective: To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population. Method: We screened a locus (rs6665) in 3’ UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese. Results: The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) 4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE 4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE 4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697). Conclusion: Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation.