title: Polymorphisms in the promoter of the human APP gene: functional evaluation and allele frequencies in Alzheimer disease.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Community study of 1013 people of white, African American, or Caribbean Hispanic ethnicity, 65 years and older, residing in northern Manhattan.
  
  
  METHODS
  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.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Eleni S
authors.initials: ES
authors.lastname: Athan
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Alex
authors.initials: A
authors.lastname: Arriaga
authors.forename: Richard P
authors.initials: RP
authors.lastname: Mayeux
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
mesh_terms: D000368:Aged; D000483:Alleles; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D016009:Chi-Square Distribution; D016001:Confidence Intervals; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured
chemical_list: D016564:Amyloid beta-Protein Precursor