Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene
Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene
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DOI：
10.1086/340733
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发表时间：
2002-06-01
影响因子：
9.8
通讯作者：
Garchon, HJ
中科院分区：
文献类型：
--
作者：
Copin, B;Brézin, AP;Garchon, HJ
原发性开角型青光眼（POAG）是一种视神经病变，在全球范围内具有很高的患病率，并显示出复杂遗传的有力证据。myocilin（MYOC）基因是迄今为止唯一一个被证明在POAG患者中存在突变的基因。载脂蛋白E（Apolipoprotein E，APOE）在脂质代谢中起重要作用，并且APOE基因参与了阿尔茨海默病（Alzheimer disease，AD）中发生的神经元变性。在这里，我们报告说，两个载脂蛋白E启动子单核苷酸多态性（SNP）以前与AD也修改POAG表型。APOE（-219G）与视神经损伤增加相关，表现为杯盘比增加和视野改变。此外，APOE（-491T）与MYOC启动子MYOC（-1000G）中的SNP以高度显著的水平相互作用，与POAG患者的眼内压（IOP）升高和降低IOP治疗的有效性有限相关。总之，这些发现确立了APOE作为POAG的有效修饰剂，这可以解释先前通过使用这种疾病的基因组扫描观察到的与染色体19 q的联系以及AD患者青光眼频率的增加。这些发现也为POAG视神经损伤和IOP调节的潜在机制提供了新的线索。
Primary open-angle glaucoma (POAG) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin (MYOC) gene is the only one that has thus far been shown to have mutations in patients with POAG. Apolipoprotein E (APOE) plays an essential role in lipid metabolism, and the APOE gene has been involved in neuronal degeneration that occurs in Alzheimer disease (AD). Here, we report that two APOE-promoter single-nucleotide polymorphisms (SNPs) previously associated with AD also modify the POAG phenotype. APOE(-219G) is associated with increased optic nerve damage, as reflected by increased cup: disk ratio and visual field alteration. In addition, APOE(-491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition and an increased frequency of glaucoma in patients with AD. The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG.