Hussman Institute for Human Genomics, University of Miami Miller School of Medicine 1501 NW 10 Ave, Miami, Florida, USA.
Neurobiol Aging. 2012 Aug;33(8):1844.e1-9. doi: 10.1016/j.neurobiolaging.2011.12.038. Epub 2012 Feb 4.
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.
针对迟发性阿尔茨海默病（AD）的遗传研究已多次将易感基因定位于包含维生素 D 受体（VDR）基因的 12q13 染色体上。流行病学研究表明，维生素 D 不足是 AD 的一个危险因素。鉴于 VDR 是维生素 D 作用的主要介质，我们试图阐明 VDR 在迟发性 AD 中的作用。我们对 492 例迟发性 AD 病例和 496 例对照进行了关联研究，共使用了 80 个标记单核苷酸多态性（SNP）。在启动子 SNP rs11568820 处发现了最强的关联（P = 9.1×10(-6)，比值比（OR）= 1.69），该 SNP 位于转录因子 Cdx-2 结合位点内，并且该 SNP 也被称为 CDX2。rs11568820 的风险等位基因与 VDR 启动子活性降低相关（p < 10(-11)）。VDR 或维生素 D 治疗过表达可抑制神经母细胞瘤细胞中的淀粉样前体蛋白（APP）转录（p < 0.001）。我们提供了统计证据和功能数据，表明 VDR 赋予 AD 的遗传风险。我们的发现与表明维生素 D 不足会增加 AD 发病风险的流行病学研究一致。
