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

Liyong Wang; Kenju Hara; Jessica M. Van Baaren; 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. Pericak-Vance; John R. Gilbert

doi:10.1016/j.neurobiolaging.2011.12.038

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

Liyong Wang, Kenju Hara, Jessica M. Van Baaren, 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. Pericak-Vance, John R. Gilbert

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1844.e1-1844.e9
Journal	Neurobiology of aging
Volume	33
Issue number	8
DOIs	https://doi.org/10.1016/j.neurobiolaging.2011.12.038
State	Published - Aug 2012

Keywords

Alzheimer's disease
Amyloid precursor protein
Association
Cdx-2
Functional polymorphism
Vitamin D receptor

ASJC Scopus subject areas

Clinical Neurology
Neuroscience(all)
Aging
Developmental Biology
Geriatrics and Gerontology

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Wang, L., Hara, K., Van Baaren, J. M., Price, J. C., Beecham, G. W., Gallins, P. J., Whitehead, P. L., Wang, G., Lu, C., Slifer, M. A., Züchner, S., Martin, E. R., Mash, D., Haines, J. L., Pericak-Vance, M. A., & Gilbert, J. R. (2012). Vitamin D receptor and Alzheimer's disease: A genetic and functional study. Neurobiology of aging, 33(8), 1844.e1-1844.e9. https://doi.org/10.1016/j.neurobiolaging.2011.12.038

Vitamin D receptor and Alzheimer's disease : A genetic and functional study. / Wang, Liyong; Hara, Kenju; Van Baaren, Jessica M.; Price, Justin C.; Beecham, Gary W.; Gallins, Paul J.; Whitehead, Patrice L.; Wang, Gaofeng; Lu, Chunrong; Slifer, Michael A.; Züchner, Stephan ; Martin, Eden R.; Mash, Deborah; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Gilbert, John R.

In: Neurobiology of aging, Vol. 33, No. 8, 08.2012, p. 1844.e1-1844.e9.

Research output: Contribution to journal › Article › peer-review

Wang, L, Hara, K, Van Baaren, JM, Price, JC, Beecham, GW, Gallins, PJ, Whitehead, PL, Wang, G, Lu, C, Slifer, MA, Züchner, S , Martin, ER, Mash, D, Haines, JL, Pericak-Vance, MA & Gilbert, JR 2012, 'Vitamin D receptor and Alzheimer's disease: A genetic and functional study', Neurobiology of aging, vol. 33, no. 8, pp. 1844.e1-1844.e9. https://doi.org/10.1016/j.neurobiolaging.2011.12.038

Wang, Liyong ; Hara, Kenju ; Van Baaren, Jessica M. ; Price, Justin C. ; Beecham, Gary W. ; Gallins, Paul J. ; Whitehead, Patrice L. ; Wang, Gaofeng ; Lu, Chunrong ; Slifer, Michael A. ; Züchner, Stephan ; Martin, Eden R. ; Mash, Deborah ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. ; Gilbert, John R. / Vitamin D receptor and Alzheimer's disease : A genetic and functional study. In: Neurobiology of aging. 2012 ; Vol. 33, No. 8. pp. 1844.e1-1844.e9.

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abstract = "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.",

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