title: The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain.
abstract: Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A -48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the -48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Abeta(40), Abeta(42(43)), and total Abeta load in AD brains. The -48 CC genotype was associated with 47% greater total Abeta load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Abeta load.
authors.affiliation: Molecular Psychiatry Department, Division of Neuroscience, Queen Elizabeth Psychiatry Hospital, University of Birmingham, Birmingham B15 2QZ, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Lambert
authors.forename: D M
authors.initials: DM
authors.lastname: Mann
authors.forename: J M
authors.initials: JM
authors.lastname: Harris
authors.forename: M C
authors.initials: MC
authors.lastname: Chartier-Harlin
authors.forename: A
authors.initials: A
authors.lastname: Cumming
authors.forename: J
authors.initials: J
authors.lastname: Coates
authors.forename: H
authors.initials: H
authors.lastname: Lemmon
authors.forename: D
authors.initials: D
authors.lastname: StClair
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: C
authors.initials: C
authors.lastname: Lendon
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053764:Presenilin-1; D011401:Promoter Regions, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1