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

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• 作者：Liyong Wang^a ; ^# ; Kenju Hara^a ; ^d ; ^# ; Jessica M. Van Baaren^a ; Justin C. Price^a ; Gary W. Beecham^a ; Paul J. Gallins^a ; Patrice L. Whitehead^a ; Gaofeng Wang^a ; Chunrong Lu^a ; Michael A. Slifer^a ; Stephan Zü ; chner^a ; Eden R. Martin^a ; Deborah Mash^b ; Jonathan L. Haines^c ; Margaret A. Pericak-Vance^a ; John R. Gilbert^a ; ^{jgilbert@med.miami.edu}
• 关键词：Alzheimer's disease ; Vitamin D receptor ; Functional polymorphism ; Amyloid precursor protein ; Association ; Cdx-2 ; Association
• 刊名：Neurobiology of Aging
• 出版年：2012
• 期刊代码：202_01974580
• 类别：med
• 出版时间：August, 2012
• 卷：33
• 期：8
• 页码：1844.e1-1844.e9
• 文件大小：1102 K

摘要

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脳10^鈭?, 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^鈭?1). 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.