Functions of intronic nucleotide variants in the gene encoding pleckstrin homology like domain beta 2 (PHLDB2) on susceptibility to vascular dementia.

OBJECTIVES:A genome-wide association study (GWAS) failed to detect any genetic associations with susceptibility to vascular dementia (VaD) by the Bonferroni multiple test. This study aimed to discover false negative associations from the GWAS. METHODS:We selected a candidate gene in which multiple associations were identified with its single nucleotide polymorphisms (SNPs). Genetic associations were intensively examined with its SNPs using 207 VaD patients and 207 age- and sex-matched control subjects. Functions of candidate SNPs on splicing of the gene were predicted by an in silico analysis and evaluated by a minigene assay. RESULTS:Genetic analysis with 80 SNPs of pleckstrin homology like domain beta 2 (PHLDB2) revealed 6 SNPs associated with VaD (P < 6.25 × 10(-4)). Among them, four SNPs in introns 2 and 3 were in complete linkage and associated also with VaD-related phenotypes (P < 0.05). Especially, rs951660 was predicted to produce splicing enhancers or serine/arginine-rich protein binding sites, and its minor allele (A) delayed expression of mRNA in vivo. CONCLUSIONS:The current study suggested a novel association of susceptibility to VaD with the gene encoding PHLDB2. The minor allele, A, of its intronic SNP 'rs951660' might induce a delayed splicing and thus increase the susceptibility to VaD.

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