Open AccessRXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism
Author(s) -
Kölsch Heike,
Lütjohann Dieter,
Jessen Frank,
Popp Julius,
Hentschel Frank,
Kelemen Peter,
Friedrichs Silvia,
Maier T.A. Wolfgang,
Heun Reinhard
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00383.x
Subject(s) - lathosterol , haplotype , medicine , endocrinology , single nucleotide polymorphism , cholesterol , biology , retinoid x receptor , nuclear receptor , gene , genetics , allele , genotype , transcription factor , sterol , campesterol
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.