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RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism

Cholesterol metabolism is altered in Alzheimer's disease (AD). The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a member of the nuclear ligand-activated transcription factor family. RXRs are key regulators of cholesterol synthesis and thus cholesterol metabolism. We performed a syst...

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Autores principales: Kölsch, Heike, Lütjohann, Dieter, Jessen, Frank, Popp, Julius, Hentschel, Frank, Kelemen, Peter, Friedrichs, Silvia, Maier, TA Wolfgang, Heun, Reinhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822518/
https://www.ncbi.nlm.nih.gov/pubmed/19374686
http://dx.doi.org/10.1111/j.1582-4934.2009.00383.x
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author Kölsch, Heike
Lütjohann, Dieter
Jessen, Frank
Popp, Julius
Hentschel, Frank
Kelemen, Peter
Friedrichs, Silvia
Maier, TA Wolfgang
Heun, Reinhard
author_facet Kölsch, Heike
Lütjohann, Dieter
Jessen, Frank
Popp, Julius
Hentschel, Frank
Kelemen, Peter
Friedrichs, Silvia
Maier, TA Wolfgang
Heun, Reinhard
author_sort Kölsch, Heike
collection PubMed
description Cholesterol metabolism is altered in Alzheimer's disease (AD). The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a member of the nuclear ligand-activated transcription factor family. RXRs are key regulators of cholesterol synthesis and thus cholesterol metabolism. We performed a systematic screen for gene variants in the RXRA gene. The effect of these gene variants on the risk of AD was investigated in 405 AD patients (mean age: 74.27 ± 9.37 years; female 78.6%) and 347 controls (mean age: 73.26 ± 8.37 years; female 57.2%). Furthermore, the influence of RXRA gene variants on CSF and plasma levels of cholesterol, lathosterol and 24S-hydroxycholesterol were evaluated. One of the identified seven SNPs in RXRA influenced AD risk in our single marker analysis (rs3132293: P= 0.006). Haplotype analysis identified a three-marker haplotype (TGC) consisting of rs3118570, rs1536475 and rs3132293, which decreased the risk of AD (P= 0.009). The single marker rs3132293 (P= 0.026) and the TGC haplotype (P= 0.026) influenced CSF lathosterol levels in non-demented controls, and cholesterol levels in the combined sample comprising AD patients and controls (Rs3132293: P= 0.050; TGC haplotype: P= 0.035). 24S-Hydroxycholesterol CSF and plasma levels were also influenced by rs3132293 (CSF: P= 0.004; plasma: P= 0.001) and the TGC haplotype (CSF: P= 0.004; plasma: P= 0.002); this effect was most pronounced in AD patients (rs3132293: CSF: P= 0.009, plasma: P= 0.002; TGC haplotype: CSF: P= 0.019, plasma: P= 0.005). Our results suggest that RXRA gene variants might act as risk factor for AD via an influence on cerebral cholesterol metabolism.
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spelling pubmed-38225182015-04-27 RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism Kölsch, Heike Lütjohann, Dieter Jessen, Frank Popp, Julius Hentschel, Frank Kelemen, Peter Friedrichs, Silvia Maier, TA Wolfgang Heun, Reinhard J Cell Mol Med Articles Cholesterol metabolism is altered in Alzheimer's disease (AD). The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a member of the nuclear ligand-activated transcription factor family. RXRs are key regulators of cholesterol synthesis and thus cholesterol metabolism. We performed a systematic screen for gene variants in the RXRA gene. The effect of these gene variants on the risk of AD was investigated in 405 AD patients (mean age: 74.27 ± 9.37 years; female 78.6%) and 347 controls (mean age: 73.26 ± 8.37 years; female 57.2%). Furthermore, the influence of RXRA gene variants on CSF and plasma levels of cholesterol, lathosterol and 24S-hydroxycholesterol were evaluated. One of the identified seven SNPs in RXRA influenced AD risk in our single marker analysis (rs3132293: P= 0.006). Haplotype analysis identified a three-marker haplotype (TGC) consisting of rs3118570, rs1536475 and rs3132293, which decreased the risk of AD (P= 0.009). The single marker rs3132293 (P= 0.026) and the TGC haplotype (P= 0.026) influenced CSF lathosterol levels in non-demented controls, and cholesterol levels in the combined sample comprising AD patients and controls (Rs3132293: P= 0.050; TGC haplotype: P= 0.035). 24S-Hydroxycholesterol CSF and plasma levels were also influenced by rs3132293 (CSF: P= 0.004; plasma: P= 0.001) and the TGC haplotype (CSF: P= 0.004; plasma: P= 0.002); this effect was most pronounced in AD patients (rs3132293: CSF: P= 0.009, plasma: P= 0.002; TGC haplotype: CSF: P= 0.019, plasma: P= 0.005). Our results suggest that RXRA gene variants might act as risk factor for AD via an influence on cerebral cholesterol metabolism. Blackwell Publishing Ltd 2009-03 2009-03-24 /pmc/articles/PMC3822518/ /pubmed/19374686 http://dx.doi.org/10.1111/j.1582-4934.2009.00383.x Text en © 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
spellingShingle Articles
Kölsch, Heike
Lütjohann, Dieter
Jessen, Frank
Popp, Julius
Hentschel, Frank
Kelemen, Peter
Friedrichs, Silvia
Maier, TA Wolfgang
Heun, Reinhard
RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title_full RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title_fullStr RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title_full_unstemmed RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title_short RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
title_sort rxra gene variations influence alzheimer's disease risk and cholesterol metabolism
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822518/
https://www.ncbi.nlm.nih.gov/pubmed/19374686
http://dx.doi.org/10.1111/j.1582-4934.2009.00383.x
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