Vitamin D receptor and Alzheimer's disease: a genetic and functional study.
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.
Hussman Institute for Human Genomics, University of Miami Miller School of Medicine 1501 NW 10 Ave, Miami, Florida, USA.
Liyong
L
Wang
Kenju
K
Hara
Jessica M
JM
Van Baaren
Justin C
JC
Price
Gary W
GW
Beecham
Paul J
PJ
Gallins
Patrice L
PL
Whitehead
Gaofeng
G
Wang
Chunrong
C
Lu
Michael A
MA
Slifer
Stephan
S
Züchner
Eden R
ER
Martin
Deborah
D
Mash
Jonathan L
JL
Haines
Margaret A
MA
Pericak-Vance
John R
JR
Gilbert
D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D000071616:CDX2 Transcription Factor; D015897:Comorbidity; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D015995:Prevalence; D018167:Receptors, Calcitriol / Q000235:genetics*; D018570:Risk Assessment; D015534:Trans-Activators / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D014808:Vitamin D Deficiency / Q000453:epidemiology* / Q000235:genetics*
D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; D015534:Trans-Activators