RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism.
RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism.
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DOI：
10.1111/j.1582-4934.2009.00383.x
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发表时间：
2009-03
影响因子：
5.3
通讯作者：
Heun R
中科院分区：
文献类型：
--
作者：
Kölsch H;Lütjohann D;Jessen F;Popp J;Hentschel F;Kelemen P;Friedrichs S;Maier TA;Heun R
阿尔茨海默病(AD)患者的胆固醇代谢发生改变。核激素受体维甲酸X受体a(RXRA)是核配体激活的转录因子家族的一员。RXRs是胆固醇合成和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的筛查。研究了405例AD患者(平均年龄：74.27±9.37岁；女性78.6%)和347例对照组(平均年龄：73.26±8.37岁；女性57.2%)AD发病风险的关系。此外，还观察了RXRA基因变异对脑脊液和血浆胆固醇、催乳素和24S-羟基胆固醇水平的影响。在我们的单标记分析中，在RXRA中识别的七个SNP中的一个影响AD风险(rs3132293：P=0.006)。单倍型分析发现由rs3118570、rs1536475和rs3132293组成的三标记单倍型降低了AD的风险(P=0.009)。单标记Rs3132293(P=0.026)和TGC单倍型(P=0.026)影响非痴呆对照组的脑脊液催乳素水平，以及AD患者和对照组的联合样本中的胆固醇水平(Rs3132293：P=0.050；TGC单倍型：P=0.035)。24S-羟基胆固醇水平也受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)的影响，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)。我们的结果提示，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。
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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