Kölsch Heike, Lütjohann Dieter, Jessen Frank, Popp Julius, Hentschel Frank, Kelemen Peter, Friedrichs Silvia, Maier T A Wolfgang, Heun Reinhard
Department of Psychiatry, University of Bonn, Bonn, Germany.
J Cell Mol Med. 2009 Mar;13(3):589-98. doi: 10.1111/j.1582-4934.2009.00383.x.
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.
阿尔茨海默病（AD）中胆固醇代谢会发生改变。核激素受体维甲酸X受体α（RXRα）是核配体激活转录因子家族的成员。RXRs是胆固醇合成以及胆固醇代谢的关键调节因子。我们对RXRA基因中的基因变异进行了系统筛查。在405例AD患者（平均年龄：74.27±9.37岁；女性占78.6%）和347名对照者（平均年龄：73.26±8.37岁；女性占57.2%）中研究了这些基因变异对AD风险的影响。此外，还评估了RXRA基因变异对脑脊液和血浆中胆固醇、羊毛甾醇和24S-羟基胆固醇水平的影响。在我们的单标记分析中，RXRA中鉴定出的七个单核苷酸多态性（SNP）之一影响AD风险（rs3132293：P = 0.006）。单倍型分析确定了一个由rs3118570、rs1536475和rs3132293组成的三标记单倍型（TGC），其降低了AD风险（P = 0.009）。单标记rs3132293（P = 0.026）和TGC单倍型（P = 0.026）影响非痴呆对照者的脑脊液羊毛甾醇水平，以及包括AD患者和对照者的合并样本中的胆固醇水平（Rs3132293：P = 0.050；TGC单倍型：P = 0.035）。rs3132293（脑脊液：P = 0.004；血浆：P = 0.001）和TGC单倍型（脑脊液：P = 0.004；血浆：P = 0.002）也影响24S-羟基胆固醇的脑脊液和血浆水平；这种影响在AD患者中最为明显（rs3132293：脑脊液：P = 0.009，血浆：P = 0.002；TGC单倍型：脑脊液：P = 0.019，血浆：P = 0.005）。我们的结果表明，RXRA基因变异可能通过影响脑胆固醇代谢而成为AD的危险因素。
