Vitamin D receptor and Alzheimer's disease: a genetic and functional study

• DOI: 10.1016/j.neurobiolaging.2011.12.038
• Publication Date: 2012-02-04T03:37:04Z
• Authors: Liyong Wang; Kenju Hara; Jessica M. Van Ba...; Justin C. Price; Gary W. Beecham; Paul J. Gallins; Patrice L. Whitehead; Gaofeng Wang; Chunrong Lu; Michael A. Slifer; Stephan Züchner; Eden R. Martin; Deborah Mash; Jonathan L. Haines; Margaret A. Peric...; John R. Gilbert
• Keywords: Homeodomain Proteins; Male; Comorbidity; Vitamin D Deficiency; Risk Assessment; United States; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Prevalence; Trans-Activators; Humans; Receptors, Calcitriol; CDX2 Transcription Factor; Female; Genetic Predisposition to Disease; Aged

Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1 × 10(-6), odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10(-11)). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.