title: Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-beta 1-42 and plasma apolipoprotein levels.
abstract: The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of beta-amyloid (Abeta) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Abeta 1-42 levels, reinforcing emerging evidence of a connection between lipid and Abeta metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Abeta 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDL-cholesterol (LDL-C) among smokers (P = 0.000055 and P = 0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus non-smokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Abeta and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.
authors.affiliation: Centre for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35, 171 77, Stockholm, Sweden.
authors.forename: Hagit
authors.initials: H
authors.lastname: Katzov
authors.affiliation: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bennet
authors.affiliation: Department of Clinical Neuroscience and Transfusion Medicine, Sahlgren's University Hospital, University of Göteborg, Göteborg, Sweden.
authors.forename: Kina
authors.initials: K
authors.lastname: Höglund
authors.affiliation: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.|Division of Coagulation Research, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Wiman
authors.affiliation: Department of Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Department of Genetics, Leicester University, Leicester, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
authors.affiliation: Neurotec, Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Department of Clinical Neuroscience and Transfusion Medicine, Sahlgren's University Hospital, University of Göteborg, Göteborg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.|Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: De Faire
authors.affiliation: Centre for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35, 171 77, Stockholm, Sweden. Jonathan.Prince@cgb.ki.se.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001053:Apolipoproteins / Q000097:blood*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D040641:Quantitative Trait Loci
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001053:Apolipoproteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)