Promoter sequence variants of LIGHT are associated with female vascular dementia

Abstract

LIGHT (homologous to Lymphotoxins, exhibits Inducible expression, and competes with herpes simplex virus Glycoprotein D for Herpes virus entry mediator, a receptor expressed by T lymphocytes) is implicated in the inflammation by disrupted T cell homeostasis, primarily at a transcriptional level. We investigated the association of LIGHT promoter with ischemic stroke and vascular dementia induced by such inflammation. We determined transcription factor binding sites altered by promoter SNPs using transcription factor prediction programs. Six common haplotypes composed of the selected SNPs (C-770T, G-607T, G-543A, and A-399G) were used for the assay of reporter activity. The most frequent haplotype construct, CGGA, induced the highest luciferase activity. The haplotype TTGA showed the lowest expression with 0.39-fold activity (P < 0.001) of CGGA. The substitution from C to T at the locus of C-770T (TGGA) decreased the reporter activity by 47% (P < 0.001). The SNPs and haplotypes were further investigated to see their association with ischemic stroke and vascular dementia in 455 controls and 478 patients. Significant association with vascular dementia was shown in the allele T of C-770T (odds ratio [OR] = 1.54; P < 0.05) and the haplotype TTGA (OR = 10.59; P < 0.05) in females. We concluded that the allele T of C-770T and the haplotype TTGA of the promoter SNPs in LIGHT gene might decrease the expression of LIGHT and subsequently increase the susceptibility to vascular dementia in females.