Polymorphisms in the promoter of the human APP gene - Functional evaluation and allele frequencies in Alzheimer disease

被引:32
作者
Athan, ES
Lee, JH
Arriaga, A
Mayeux, RP
Tycko, B
机构
[1] Columbia Univ, Gertrude H Sergievsky Ctr, Coll Phys & Surg, New York, NY 10032 USA
[2] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[3] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA
[4] Columbia Univ, Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA
关键词
D O I
10.1001/archneur.59.11.1793
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
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页码:1793 / 1799
页数:7
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