Ingelsson Martin, Jesneck Jennifer, Irizarry Michael C, Hyman Bradley T, Rebeck G William
Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Neurosci Lett. 2004 Sep 2;367(2):228-31. doi: 10.1016/j.neulet.2004.06.011.
An association was recently reported between an increased risk of Alzheimer's disease and an intron 2 AA genotype of CYP46, the enzyme hydroxylating cholesterol to 24S-hydroxycholesterol. Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-beta and tau in brain and cerebrospinal fluid. We determined the CYP46 intron 2 genotype in a cohort of 178 AD and 105 non-demented control subjects, but found no significant association with AD for any of the individual genotypes or alleles. Further, in an autopsy confirmed subset of this cohort, the proposed CYP46 risk genotype was not associated with any increase in the brain levels of amyloid-beta40, amyloid-beta42 or in the levels of amyloid plaques and neurofibrillary tangles. Despite growing evidence implicating cholesterol metabolism in AD risk and Abeta generation, our data does not support a robust genetic relationship between the CYP46 intron 2 polymorphism and AD risk or neuropathology.
最近有报道称，阿尔茨海默病风险增加与CYP46（一种将胆固醇羟基化为24S - 羟基胆固醇的酶）的内含子2 AA基因型之间存在关联。此外，发现携带CYP46 AA基因型的个体大脑和脑脊液中的β淀粉样蛋白和tau蛋白水平升高。我们在一个由178名阿尔茨海默病患者和105名非痴呆对照受试者组成的队列中确定了CYP46内含子2的基因型，但未发现任何个体基因型或等位基因与阿尔茨海默病有显著关联。此外，在该队列经尸检证实的一个亚组中，所提出的CYP46风险基因型与大脑中β淀粉样蛋白40、β淀粉样蛋白42水平的升高以及淀粉样斑块和神经原纤维缠结的水平均无关联。尽管越来越多的证据表明胆固醇代谢与阿尔茨海默病风险及β淀粉样蛋白生成有关，但我们的数据并不支持CYP46内含子2多态性与阿尔茨海默病风险或神经病理学之间存在紧密的遗传关系。
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