title: Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.
abstract: 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.
authors.affiliation: Oxford Project to Investigate Memory and Ageing, University Department of Physiology, Anatomy and Genetics, Oxford, UK. donald.lehmann@pharm.ox.ac.uk
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Lehmann
authors.forename: Maaike
authors.initials: M
authors.lastname: Schuur
authors.forename: Donald R
authors.initials: DR
authors.lastname: Warden
authors.forename: Naomi
authors.initials: N
authors.lastname: Hammond
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lehmann
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.forename: Kristelle
authors.initials: K
authors.lastname: Brown
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Chris M
authors.initials: CM
authors.lastname: Morris
authors.forename: Rachel
authors.initials: R
authors.lastname: Barker
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vásquez
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.forename: Monique M
authors.initials: MM
authors.lastname: Breteler
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Oulhaj
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Mario
authors.initials: M
authors.lastname: Cortina-Borja
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Kathryn
authors.initials: K
authors.lastname: Robson
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000209:etiology* / Q000517:prevention & control; D053327:Apolipoprotein E4 / Q000235:genetics; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007502:Iron Chelating Agents / Q000627:therapeutic use; D019190:Iron Overload / Q000150:complications* / Q000235:genetics* / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D012306:Risk; D014168:Transferrin / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D014168:Transferrin