Kölsch Heike, Lütjohann Dieter, Jessen Frank, Popp Julius, Hentschel Frank, Kelemen Peter, Schmitz Sandra, Maier Wolfgang, Heun Reinhard
Department of Psychiatry, University of Bonn, Germany.
Eur Psychiatry. 2009 Apr;24(3):183-90. doi: 10.1016/j.eurpsy.2008.12.005. Epub 2009 Mar 16.
Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer's disease (AD) and results are contradictory.
We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.
Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p=0.016; rs4900442: p=0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p=0.006). Haplotypes including both SNPs were calculated and haplotype G-C was identified to influence the risk of AD (p=0.005). AD patients and non-demented controls, who were carriers of the G-C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p=0.001) and cholesterol (p<0.001).
Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.
胆固醇24S-羟化酶（CYP46）催化胆固醇转化为24S-羟基胆固醇，这是大脑中胆固醇的主要清除产物。关于CYP46基因（CYP46A1）中只有少数基因变异作为阿尔茨海默病（AD）的遗传危险因素的相关性进行了研究，结果相互矛盾。
我们对CYP46A1进行了基因变异性筛查，并研究了基因变异对AD风险以及脑脊液中胆固醇和24S-羟基胆固醇水平的影响。
在我们的研究中，CYP46A1中鉴定出的16个单核苷酸多态性（SNP）中有两个影响AD风险（rs7157609：p = 0.016；rs4900442：p = 0.019）。这两个SNP的相互作用项也与AD风险增加相关（p = 0.006）。计算了包括这两个SNP的单倍型，确定单倍型G-C影响AD风险（p = 0.005）。携带G-C单倍型的AD患者和非痴呆对照者脑脊液中24S-羟基胆固醇水平降低（p = 0.001），胆固醇水平降低（p < 0.001）。
我们的结果表明，CYP46A1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。
