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A Multi-Center Study of ACE and the Risk of Late-Onset Alzheimer's Disease

Article type: Research Article

Authors: Belbin, Oliviaa; b; 1 | Brown, Kristellea; 1 | Shi, Huia | Medway, Christophera | Abraham, Richardc | Passmore, Peterd | Mann, Davide | Smith, A. Davidf | Holmes, Cliveg | McGuinness, Bernadetted | Craig, Davidd | Warden, Donaldg | Heun, Reinhardh | Kölsch, Heikei | Love, Sethj | Kalsheker, Noora | Williams, Juliec | Owen, Michael J.c | Carrasquillo, Minervab | Younkin, Stevenb | Morgan, Kevina; 2; * | Kehoe, Patrick G.j; 2

Affiliations: [a] Department of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK | [b] Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA | [c] Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK | [d] Department of Geriatric Medicine, The Queen's University of Belfast, Belfast, UK | [e] Greater Manchester Neurosciences Centre, University of Manchester, Manchester, UK | [f] Memory Assessment and Research Centre, University of Southampton, Southampton, UK | [g] OPTIMA, University Department of Pharmacology, Oxford, UK | [h] Department of Old Age Psychiatry, Queen Elizabeth Psychiatric Hospital, Birmingham, UK | [i] University of Bonn, Bonn, Germany | [j] School of Clinical Science, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Bristol, UK

Correspondence: [*] Correspondence to: Kevin Morgan. E-mail: Kevin.Morgan@nottingham.ac.uk.

Note: [1] These authors contributed equally to this work.

Note: [2] These authors were both principal investigators for this study.

Keywords: Alzheimer's disease, angiotensin-1 converting enzyme, haplotype, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101914

Journal: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 587-597, 2011

Accepted 28 December 2010
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Published: 10 May 2011
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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.

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