Association of SPHK1 polymorphisms with Alzheimer's disease susceptibility: Functional impact of the rs2247856 SNP on transcriptional efficiency

INTRODUCTION: Sphingosine kinase 1 (SPHK1) has been implicated in the regulation of pro-resolving lipid mediators relevant to neuroinflammation in Alzheimer's disease (AD). However, no studies have evaluated the genetic association between SPHK1 polymorphisms and AD susceptibility. METHODS: We analyzed genotype and allele frequencies of polymorphisms in the SPHK1 gene between patients with AD and healthy controls. In addition, transcription factor binding sites were evaluated. Furthermore, promoter activities associated with rs2247856 single nucleotide polymorphism (SNP) were assessed using a luciferase reporter assay. RESULTS: Among the identified SNPs, the genotype distribution of rs2247856 showed a significant association with AD. Haplotype analysis revealed that haplotype 3 (CAGTACGG) was significantly more frequent in patients with AD than in controls. Profiler of Multi-Omics Data (PROMO) analysis suggested that the rs2247856 A allele disrupts the activating transcription factor 3 transcription factor binding site. Luciferase assays demonstrated significantly reduced promoter activity in constructs containing the A allele compared to the G allele (p < 0.001), indicating allele-specific regulation of SPHK1 transcription. DISCUSSION: Our findings identify rs2247856 as a functional regulatory SNP in the SPHK1 gene associated with AD susceptibility. The reduced transcriptional activity of the A allele may impair SPHK1-mediated anti-inflammatory signaling, potentially contributing to AD pathogenesis.