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Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project

Lookup NU author(s): Dr Christopher Morris, Dr Reinhard Heun


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Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOE epsilon 4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases. (C) 2012 Elsevier Inc. All rights reserved.

Publication metadata

Author(s): Lehmann DJ, Schuur M, Warden DR, Hammond N, Belbin O, Kolsch H, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, Morris CM, Barker R, Coto E, Alvarez V, Deloukas P, Mateo I, Gwilliam R, Combarros O, Arias-Vasquez A, Aulchenko YS, Ikram MA, Breteler MM, van Duijn CM, Oulhaj A, Heun R, Cortina-Borja M, Morgan K, Robson K, Smith AD

Publication type: Article

Publication status: Published

Journal: Neurobiology of Aging

Year: 2012

Volume: 33

Issue: 1

Pages: 202.e1

Print publication date: 02/09/2010

ISSN (print): 0197-4580

ISSN (electronic): 1558-1497

Publisher: Elsevier Inc.


DOI: 10.1016/j.neurobiolaging.2010.07.018


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Funder referenceFunder name
Department of Health's NIHR Biomedical Research Centres
Erasmus Medical Center and Erasmus University, Rotterdam
European Commission (DG XII)
Ministry of Education, Culture and Science
Municipality of Rotterdam
Ministry for Health, Welfare and Sports
Moulton Charitable Foundation
Netherlands Organization for the Health Research and Development (ZonMw)
NIHR Biomedical Research Centre, Oxford
175.010.2005.011Netherlands Organisation of Scientific Research NWO
911-03-012Netherlands Organisation of Scientific Research NWO
G0400546Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health
RIDE2Research Institute for Diseases in the Elderly
RIDE1Research Institute for Diseases in the Elderly