Polymorphisms in the promoter of the human APP gene - Functional evaluation and allele frequencies in Alzheimer disease
Polymorphisms in the promoter of the human APP gene - Functional evaluation and allele frequencies in Alzheimer disease
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DOI：
10.1001/archneur.59.11.1793
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发表时间：
2002-11-01
影响因子：
--
通讯作者：
Tycko, B
中科院分区：
文献类型：
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作者：
Athan, ES;Lee, JH;Tycko, B
背景：淀粉样蛋白前体蛋白（APP）基因错义突变可导致早发性阿尔茨海默病（AD）。然而，APP调控序列多态性对AD易感性的影响尚不清楚。目的：鉴定APP启动子的多态性，测试这些多态性与AD的相关性，并评估它们对转染细胞中APP启动子活性的影响。背景：对居住在曼哈顿北部65岁及以上的1013名白人、非裔美国人或加勒比西班牙裔的社区研究。主要观察指标：通过严格的检查确定AD的诊断。标准，7年以上多次随访检查。结果：我们在APP启动子中发现了2个多态性：相对于转录起始位点，一个罕见的G- >C变异位于-9，一个频繁的G- >C变异位于+37。+37C等位基因在非裔美国患者中最常见（18%），其次是加勒比西班牙裔患者（10%）和欧洲血统的白人患者（3%）。与老年对照相比，该等位基因在AD患者中的比例过高（优势比[OR]， 1.57；在联合种族组中，95%可信区间[CI]， 1.08-2.27），但在调整了年龄、性别和教育程度后，这一比例不显著（OR, 1.41; 95% CI, 0.93-2.12）。在缺乏任何载脂蛋白e - epsilon4等位基因的参与者中发现了更强的相关性（OR, 2.12; 95% CI, 1.36-3.32[单变量分析]；OR, 2.08; 95% CI, 1.26-3.45，在调整了年龄、性别和教育程度后）。-9C等位基因的频率不足以评估其与疾病的关联。在U-87胶质瘤细胞中对这两种变异进行了启动子报告试验，未检测到启动子活性的差异。结论：-9G/C和+37G/C APP启动子多态性不太可能对AD的易感性产生强烈影响，也不可能导致APP表达的重大差异，但+37C等位基因与AD的关联值得在更大的人群样本中进一步研究。
Background: Missense mutations in the amyloid precursor protein (APP) gene cause early-onset Alzheimer disease (AD). However, little is known regarding the effects of polymorphisms in regulatory sequences of APP on AD susceptibility.Objectives: To identify polymorphisms in the APP promoter, to test these for associations with AD, and to assess their influence on APP promoter activity in transfected cells.Setting: Community study of 1013 people of white, African American, or Caribbean Hispanic ethnicity, 65 years and older, residing in northern Manhattan.Main Outcome Measures: The diagnosis of AD was established by stringent. criteria, with multiple follow-up examinations over 7 years.Results: We identified 2 polymorphisms in the APP promoter: a rare G-->C variant at -9 and a frequent G-->C variant at +37 relative to the transcription start site. The +37C allele was most frequent in African American patients (18% frequency), followed by Caribbean Hispanic patients (10%) and white patients of European descent (3%). This allele was overrepresented among patients with AD compared with elderly controls (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.08-2.27 in the combined ethnic groups), but this was not significant after adjusting for age, sex, and education (OR, 1.41; 95% CI, 0.93-2.12). A stronger association was found in participants lacking any apolipoprotein-E epsilon4 allele (OR, 2.12; 95% CI, 1.36-3.32 [univariate analysis]; OR, 2.08; 95% CI, 1.26-3.45 after adjusting for age, sex, and education). The -9C allele was not frequent enough to be evaluated for a disease association. Both variants were tested in promoter-reporter assays in U-87 glioma cells, and no differences in promoter activity were detected.Conclusions: The -9G/C and +37G/C APP promoter polymorphisms are unlikely to contribute strongly to AD susceptibility or to cause major differences in APP expression, but the +37C allele warrants further study for association with AD in larger population samples.