The purpose of this study is to investigate the correlation between single-nucleotide polymorphism (SNP) at the 3' end of the untranslated region (UTR) of Sirtuin 2 (SIRT2) gene and the risk of developing Alzheimer's disease (AD), and to explore its underlying mechanisms. In total, 260 patients with AD and 260 healthy controls were recruited in this study. The genotype of rs2015 and rs2241703 loci of the SIRT2 gene was analyzed by Sanger sequencing for all participants. Quantitative real-time Polymerase chain reaction (qRT-PCR) was used to analyze microRNAs (miRNAs) and SIRT2 mRNA levels. Western blotting was used to analyze the expression level of SIRT2 protein. The dual luciferase reporter gene assay and cell transfection were performed to examine the role of miRNAs in regulating SIRT2 expression. Carriers of the SIRT2 gene rs2015 locus A allele were 0.69 times less likely to develop AD than the carriers of the C allele (95% confidence interval (CI): 0.59-0.80, p < 0.01). The carriers of the SIRT2 gene rs2241703 locus A allele were 1.43 times more likely to develop AD than the carriers of the G allele (95% CI: 1.23-1.61, p < 0.01). The rs2015 locus single-nucleotide polymorphism (SNP) affected the binding efficiency between miR-376a-5p and miR-8061 and the 3'UTR of the SIRT2 gene, and miR-376a-5p and miR-8061 bound to SIRT2 rs2015 A allele to down-regulate the expression of the SIRT2 protein. The rs2241703 SNP affected the binding efficiency between miR-486-3p and the 3'UTR of SIRT2 gene, and miR-486-3p bound to SIRT2 rs2241703 A allele to down-regulate SIRT2 protein expression. The SIRT2 gene rs2015 and rs2241703 loci SNPs are associated with the risk of AD. The rs2015 locus SNP affects regulation of miR-376a-5p and miR-8061 in SIRT2 expression and the rs2241703 locus SNP affects regulation of miR-486-3p in SIRT2, but further studies are needed to verify this mechanism.
Keywords: Alzheimer’s disease; SIRT2; Single-nucleotide polymorphism; miRNAs.