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. 2009 Mar;13(3):589-98.
doi: 10.1111/j.1582-4934.2009.00383.x.

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

Heike Kölsch  1 , Dieter Lütjohann, Frank Jessen, Julius Popp, Frank Hentschel, Peter Kelemen, Silvia Friedrichs, T A Wolfgang Maier, Reinhard Heun
Affiliations

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

Heike Kölsch et al. J Cell Mol Med. 2009 Mar.

Abstract

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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Figures

1
1
Schematic representation of the RXRA gene and localization of the identified gene variants.
2
2
Linkage Disequilibrium (LD) structure of RXRA gene variations. The number at the intersection of each pair of SNPs represents the pairwise D' values between two SNPs.
See this image and copyright information in PMC

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