TY - JOUR
T1 - Transferrin and HFE genes interact in Alzheimer's disease risk
T2 - The Epistasis Project
AU - Lehmann, Donald J.
AU - Schuur, Maaike
AU - Warden, Donald R.
AU - Hammond, Naomi
AU - Belbin, Olivia
AU - Kölsch, Heike
AU - Lehmann, Michael G.
AU - Wilcock, Gordon K.
AU - Brown, Kristelle
AU - Kehoe, Patrick G.
AU - Morris, Chris M.
AU - Barker, Rachel
AU - Coto, Eliecer
AU - Alvarez, Victoria
AU - Deloukas, Panos
AU - Mateo, Ignacio
AU - Gwilliam, Rhian
AU - Combarros, Onofre
AU - Arias-Vásquez, Alejandro
AU - Aulchenko, Yurii S.
AU - Ikram, M. Arfan
AU - Breteler, Monique M.
AU - van Duijn, Cornelia M.
AU - Oulhaj, Abderrahim
AU - Heun, Reinhard
AU - Cortina-Borja, Mario
AU - Morgan, Kevin
AU - Robson, Kathryn
AU - Smith, A. David
N1 - Funding Information:
We are most grateful to the Moulton Charitable Foundation for a grant to fund the Epistasis Project, to all those who have provided support for the individual clinical studies, and to the Alzheimer's Research Trust and the Thomas Willis Oxford Brain Collection for tissue for DNA extraction. We warmly thank Dr. Jane Karlsson for several very helpful conversations about iron mismetabolism in brain disease. We are most grateful to Dr. John Kauwe for sharing prepublication data from his study ( Kauwe, et al., 2010 ). G.W. was partly funded by the NIHR Biomedical Research Centre, Oxford. UCL Institute of Child Health receives funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics also benefits from funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health ( G0400546 ). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE1 and 2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011 , 911-03-012 ).
PY - 2012/1
Y1 - 2012/1
N2 - 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 APOEε4 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.
AB - 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 APOEε4 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.
KW - Apolipoprotein E ε4
KW - Glycosylation
KW - Iron chelation
KW - Microglia
KW - Mild cognitive impairment
KW - Neurodegeneration
KW - Onset age
KW - Transferrin saturation
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UR - http://www.scopus.com/inward/citedby.url?scp=81355123253&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2010.07.018
DO - 10.1016/j.neurobiolaging.2010.07.018
M3 - Article
C2 - 20817350
AN - SCOPUS:81355123253
SN - 0197-4580
VL - 33
SP - 202.e1-202.e13
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 1
ER -