title: ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease.
abstract: Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimer's disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence. Based on these data, we postulated that genetic variation in the related and brain-specific ABCA2 gene leads to increase risk of AD. A large case-control study was conducted where the sample was randomly divided into a hypothesis-testing sample (230 cases/286 controls) and a validation sample (210 cases/233 controls). Among the 45 SNPs we tested, one synonymous SNP (rs908832) was found significantly associated with AD in both samples. Additional analyses performed on the whole sample showed a very strong association between this marker and early-onset AD (OR = 3.82, 95% C.I. = [2.00 - 7.30], P = 5 x 10(-5)). Further research is needed to understand the functional role of this polymorphism. However, together with the reported associations of AD with APOE, CYP46A1 and ABCA1, the present result adds a very significant support for the role of cholesterol and phospholipid homeostasis in AD and a rationale for testing novel cholesterol homeostasis-related therapeutic strategies in AD.
authors.affiliation: Aventis Pharma, Evry Genetics Center and Neurodegenerative Disease Group, Paris Research Center, 94400 Vitry-sur-Seine, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Macé
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cousin
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ricard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Spanakis
authors.forename: Carole
authors.initials: C
authors.lastname: Lafargue-Soubigou
authors.forename: Bérengère
authors.initials: B
authors.lastname: Génin
authors.forename: Raphaël
authors.initials: R
authors.lastname: Fournel
authors.forename: Sandrine
authors.initials: S
authors.lastname: Roche
authors.forename: Gilles
authors.initials: G
authors.lastname: Haussy
authors.forename: Florence
authors.initials: F
authors.lastname: Massey
authors.forename: Stéphane
authors.initials: S
authors.lastname: Soubigou
authors.forename: Georges
authors.initials: G
authors.lastname: Bréfort
authors.forename: Patrick
authors.initials: P
authors.lastname: Benoit
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Melvyn
authors.initials: M
authors.lastname: Hollis
authors.forename: Laurent
authors.initials: L
authors.lastname: Pradier
authors.forename: Jésus
authors.initials: J
authors.lastname: Benavides
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005602:France / Q000453:epidemiology; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors; D044465:White People / Q000235:genetics
chemical_list: C418186:ABCA2 protein, human; D018528:ATP-Binding Cassette Transporters; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D005819:Genetic Markers; D002784:Cholesterol