title: A multi-center study of ACE and the risk of late-onset Alzheimer's disease.
abstract: A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.
authors.affiliation: Department of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Kristelle
authors.initials: K
authors.lastname: Brown
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.forename: Richard
authors.initials: R
authors.lastname: Abraham
authors.forename: Peter
authors.initials: P
authors.lastname: Passmore
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: Bernadette
authors.initials: B
authors.lastname: McGuinness
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.forename: Donald
authors.initials: D
authors.lastname: Warden
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Minerva
authors.initials: M
authors.lastname: Carrasquillo
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D015201:Meta-Analysis as Topic; D009656:North America / Q000453:epidemiology; D016017:Odds Ratio; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D007703:Peptidyl-Dipeptidase A