Functional characterization of three single-nucleotide polymorphisms present in the human APOε promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions

Bryan Maloney, Yuan Wen Ge, Ronald C. Petersen, John Hardy, Jack T. Rogers, Jordi Pérez-Tur, Debomoy K. Lahiri

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer's disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at - 491 (A/T), - 427 (T/C), and at - 219 (G/T) upstream from the +1 transcription start site. The - 219 and - 491 polymorphic variations have significant association with instance of AD, and - 491AA has significant risk even when stratified for the APOEε4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The - 491 and - 219 polymorphisms may have an interactive effect in addition to any independent activity. DNA - protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the - 491 and - 219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA - protein interactions in cell culture-based as-says. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEε4 allele status.

Original languageEnglish (US)
Pages (from-to)185-201
Number of pages17
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume153
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Aging
  • Alzheimer's disease
  • Dementia
  • Gene regulation
  • Genetics

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Functional characterization of three single-nucleotide polymorphisms present in the human APOε promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions'. Together they form a unique fingerprint.

  • Cite this