title: BACE1 polymorphisms do not influence platelet membrane beta-secretase activity or genetic susceptibility for Alzheimer's disease in the Northern Irish population.
abstract: Beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). BACE1 is a protease that catalyses APP cleavage at the beta-secretase site. We evaluated all common and putatively functional polymorphisms in the genomic region encompassing BACE1 for an association with AD, and for functional effects on platelet beta-secretase activity. Tag SNPs (n = 10) derived from phase II of the International HapMap Project, and a nonsynonymous variant, were successfully genotyped in 901 Caucasian individuals from Northern Ireland using Sequenom iPLEX and TaqMan technologies. APOE genotyping was performed by PCR-RFLP. Platelet membrane beta-secretase activity was assayed in a subset of individuals (n = 311). Hardy-Weinberg equilibrium was observed for all variants. Evidence for an association with AD was observed with multi-marker haplotype analyses (P = 0.01), and with rs676134 when stratified for APOE genotype (P = 0.02), however adjusting for multiple testing negated the evidence for association of this variant with AD. chi(2) analysis of genotype and allele frequencies in cases versus controls for individual SNPs revealed no evidence for association (5% level). No genetic factors were observed that significantly influenced platelet membrane beta-secretase activity. We have selected an appropriate subset of variants suitable for comprehensive genetic investigation of the BACE1 gene. Our results suggest that common BACE1 polymorphisms and putatively functional variants have no significant influence on genetic susceptibility to AD, or platelet beta-secretase activity, in this Caucasian Northern Irish population.
authors.affiliation: Division of Psychiatry and Neuroscience, School of Medicine and Dentistry, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: S
authors.initials: S
authors.lastname: Todd
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
authors.forename: W W
authors.initials: WW
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Carson
authors.forename: S
authors.initials: S
authors.lastname: Heggarty
authors.forename: B
authors.initials: B
authors.lastname: McGuinness
authors.forename: G B
authors.initials: GB
authors.lastname: Irvine
authors.forename: D
authors.initials: D
authors.lastname: Craig
authors.forename: A P
authors.initials: AP
authors.lastname: Passmore
authors.forename: J A
authors.initials: JA
authors.lastname: Johnston
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001792:Blood Platelets / Q000201:enzymology*; D002462:Cell Membrane / Q000201:enzymology*; D004252:DNA Mutational Analysis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D009660:Northern Ireland / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D005819:Genetic Markers; C040661:apolipoprotein E1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human