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

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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.

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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10.1016/j.neurobiolaging.2011.12.038

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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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title = "Vitamin D receptor and Alzheimer's disease: A genetic and functional study",

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.",

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

author = "Liyong Wang and Kenju Hara and {Van Baaren}, {Jessica M.} and Price, {Justin C.} and Beecham, {Gary W.} and Gallins, {Paul J.} and Whitehead, {Patrice L.} and Gaofeng Wang and Chunrong Lu and Slifer, {Michael A.} and Stephan Z{\"u}chner and Martin, {Eden R.} and Deborah Mash and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Gilbert, {John R.}",

note = "Funding Information: The first two authors contributed equally to this work. We thank the Alzheimer's disease (AD) patients and their families for participating in our study. We also thank the laboratory staff of the Hussman Institute for Human Genomics; particularly Christina Siebert, Odette Davis, and Daniela Martinez. We thank T. Ikeuchi, MD, PhD at the Department of Molecular Neuroscience, Center for Bioresources, Niigata University (Niigata, Japan) for comments and advice. This study was supported by Alzheimer's Association grant ( IIRG-05-14147 ). ",

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AU - Wang, Liyong

AU - Hara, Kenju

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AU - Price, Justin C.

AU - Beecham, Gary W.

AU - Gallins, Paul J.

AU - Whitehead, Patrice L.

AU - Wang, Gaofeng

AU - Lu, Chunrong

AU - Slifer, Michael A.

AU - Züchner, Stephan

AU - Martin, Eden R.

AU - Mash, Deborah

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Gilbert, John R.

N1 - Funding Information: The first two authors contributed equally to this work. We thank the Alzheimer's disease (AD) patients and their families for participating in our study. We also thank the laboratory staff of the Hussman Institute for Human Genomics; particularly Christina Siebert, Odette Davis, and Daniela Martinez. We thank T. Ikeuchi, MD, PhD at the Department of Molecular Neuroscience, Center for Bioresources, Niigata University (Niigata, Japan) for comments and advice. This study was supported by Alzheimer's Association grant ( IIRG-05-14147 ).

PY - 2012/8

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N2 - 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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Vitamin D receptor and Alzheimer's disease: A genetic and functional study

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Keywords

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