Polymorphisms in the promoter of the human APP gene: functional evaluation and allele frequencies in Alzheimer disease.

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.

[1]  D. Knook,et al.  Association of APOE e2/e3/e4 and Promoter Gene Variants With Dementia But Not Cardiovascular Mortality in Old Age , 2002 .

[2]  E. Hawe,et al.  The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. , 2001, European heart journal.

[3]  J. H. Lee,et al.  A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. , 2001, JAMA.

[4]  A. Hofman,et al.  Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer's Disease , 2001, Journal of Neurology.

[5]  Á. Pascual,et al.  Brain‐derived neurotrophic factor stimulates β‐amyloid gene promoter activity by a Ras‐dependent/AP‐1‐independent mechanism in SH‐SY5Y neuroblastoma cells , 2001, Journal of neurochemistry.

[6]  D. Selkoe.  Presenilin, Notch, and the genesis and treatment of Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Tycko,et al.  Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome , 2001, Neuroscience Letters.

[8]  K. Ihara,et al.  Association of IFN-γ and IFN regulatory factor 1 polymorphisms with childhood atopic asthma , 2001 .

[9]  P. S. St George-Hyslop.  Genetic Factors in the Genesis of Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[10]  C. Bouchard,et al.  Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[11]  C. Broeckhoven,et al.  Transcriptional regulation of Alzheimer's disease genes: implications for susceptibility. , 2000, Human molecular genetics.

[12]  B. Gitter,et al.  Regulation of amyloid precursor protein processing by Aβ in human glioma cells , 2000, Neurobiology of Aging.

[13]  S. Gandy,et al.  Regulation of alzheimer beta-amyloid precursor trafficking and metabolism. , 2000, Advances in experimental medicine and biology.

[14]  F. Leuven,et al.  Single and multiple transgenic mice as models for Alzheimer’s disease , 2000, Progress in Neurobiology.

[15]  D. Lahiri,et al.  Analysis of the 5'-flanking region of the beta-amyloid precursor protein gene that contributes to increased promoter activity in differentiated neuronal cells. , 2000, Brain research. Molecular brain research.

[16]  C. Duijn,et al.  Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. , 2000, Human molecular genetics.

[17]  A. Hamsten,et al.  Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[18]  A. Hofman,et al.  Genetic association of the presenilin-1 regulatory region with early-onset Alzheimer's disease in a population-based sample , 1999, European Journal of Human Genetics.

[19]  B. Hyman,et al.  Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease , 1999, Neuroscience Letters.

[20]  D. Lahiri,et al.  Promoter activity of the beta-amyloid precursor protein gene is negatively modulated by an upstream regulatory element. , 1999, Brain research. Molecular brain research.

[21]  M. Owen,et al.  Genetic variability at the amyloid-β precursor protein locus may contribute to the risk of late-onset Alzheimer's disease , 1999, Neuroscience Letters.

[22]  T. Kubota,et al.  Production of amyloid beta protein precursor as a proteinase inhibitor by human astrocytic tumors. , 1999, Anticancer research.

[23]  D. Selkoe,et al.  Enhancer function and novel DNA binding protein activity in the near upstream betaAPP gene promoter. , 1999, Gene.

[24]  L. Harrell,et al.  Polymorphic tetranucleotide repeat site within intron 7 of the β-amyloid precursor protein gene and its lack of association with Alzheimer’s disease , 1998, Human Genetics.

[25]  J. Hardy,et al.  Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease. , 1998, Human molecular genetics.

[26]  A. M. Szczepanik,et al.  Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. , 1998, Brain research. Molecular brain research.

[27]  A. Roses.  Apolipoprotein E, a Gene with Complex Biological Interactions in the Aging Brain , 1997, Neurobiology of Disease.

[28]  Amanda J. Wilson,et al.  Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele , 1997, Nature Genetics.

[29]  H. Mcdevitt,et al.  Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Borchelt,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.

[31]  R. Kraus,et al.  The Initiator Element and Proximal Upstream Sequences Affect Transcriptional Activity and Start Site Selection in the Amyloid β-Protein Precursor Promoter* , 1996, The Journal of Biological Chemistry.

[32]  B. Tycko,et al.  Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer’s disease , 1996, Human Genetics.

[33]  M. Memo,et al.  Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures* , 1996, The Journal of Biological Chemistry.

[34]  P. Malherbe,et al.  Lack of β-Amyloidosis in transgenic mice expressing low levels of familial Alzheimer's disease missense mutations , 1996, Neurobiology of Aging.

[35]  M. Memo,et al.  Identification and Characterization of a κB/Rel Binding Site in the Regulatory Region of the Amyloid Precursor Protein Gene (*) , 1995, The Journal of Biological Chemistry.

[36]  R. Bayney,et al.  Transcriptional activation of Alzheimer's beta-amyloid precursor protein gene by stress. , 1995, Brain research. Molecular brain research.

[37]  D. Lahiri,et al.  Promoter activity of the gene encoding the beta-amyloid precursor protein is up-regulated by growth factors, phorbol ester, retinoic acid and interleukin-1. , 1995, Brain research. Molecular brain research.

[38]  K. Wisniewski,et al.  Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer's disease and Down's syndrome brain , 1995, Brain Research.

[39]  M. Owen,et al.  No evidence that common allelic variation in the Amyloid Precursor Protein (APP) gene confers susceptibility to Alzheimer's disease. , 1995, Human molecular genetics.

[40]  J. Trejo,et al.  A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. , 1994, The Journal of biological chemistry.

[41]  W. Quitschke.  Two nuclear factor binding domains activate expression from the human amyloid beta-protein precursor promoter. , 1994, The Journal of biological chemistry.

[42]  D. Graham,et al.  β-Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury , 1993, Neuroscience Letters.

[43]  D. Goldgaber,et al.  The amyloid beta-protein precursor promoter. A region essential for transcriptional activity contains a nuclear factor binding domain. , 1992, The Journal of biological chemistry.

[44]  R. Mayeux,et al.  Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. , 1992, Archives of neurology.

[45]  M. Hattori,et al.  Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse. , 1992, Gene.

[46]  N. Robakis,et al.  The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences. , 1991, Brain research. Molecular brain research.

[47]  H. W. Harris,et al.  Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[48]  H. Wiśniewski,et al.  Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome , 1985, Annals of neurology.

[49]  C. P. Hughes,et al.  A New Clinical Scale for the Staging of Dementia , 1982, British Journal of Psychiatry.

[50]  D. Knook,et al.  Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age. , 2002, American journal of medical genetics.

[51]  H. Saito,et al.  Interferon regulatory factor 1 promoter polymorphism and response to type 1 interferon , 2001, Journal of cellular biochemistry. Supplement.

[52]  S. Gandy,et al.  Regulation of Alzheimer -amyloid precursor trafficking and metabolism 1 1 Portions of this review h , 2000 .

[53]  Xin Chen,et al.  TRANSFAC: an integrated system for gene expression regulation , 2000, Nucleic Acids Res..

[54]  B. Tycko,et al.  Erratum: Polymorphisms in the human apolipoprotein-J/clusterin gene: Ethnic variation and distribution in Alzheimer's disease (Human Genetics (1996) 98 (430-436)) , 1998 .

[55]  J. Nalbantoglu,et al.  The helix-loop-helix transcription factor USF interacts with the basal promoter of human amyloid precursor protein. , 1996, Brain research. Molecular brain research.

[56]  N. Schupf,et al.  Prevalence of dementia in adults with and without Down syndrome. , 1996, American journal of mental retardation : AJMR.

[57]  A. Goate,et al.  Role of the beta-amyloid precursor protein in Alzheimer's disease. , 1994, Trends in biochemical sciences.

[58]  A. Goate,et al.  Role of the β-amyloid precursor protein in Alzheimer's disease , 1994 .

[59]  D. Graham,et al.  Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. , 1993, Neuroscience letters.

[60]  B. Hyman.  Down syndrome and Alzheimer disease. , 1992, Progress in clinical and biological research.

[61]  Hyman Bt.  Down syndrome and Alzheimer disease. , 1992 .