Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.
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.
Lehmann
Donald J
DJ
Oxford Project to Investigate Memory and Ageing, University Department of Physiology, Anatomy and Genetics, Oxford, UK. donald.lehmann@pharm.ox.ac.uk
Schuur
Maaike
M
Warden
Donald R
DR
Hammond
Naomi
N
Belbin
Olivia
O
Kölsch
Heike
H
Lehmann
Michael G
MG
Wilcock
Gordon K
GK
Brown
Kristelle
K
Kehoe
Patrick G
PG
Morris
Chris M
CM
Barker
Rachel
R
Coto
Eliecer
E
Alvarez
Victoria
V
Deloukas
Panos
P
Mateo
Ignacio
I
Gwilliam
Rhian
R
Combarros
Onofre
O
Arias-Vásquez
Alejandro
A
Aulchenko
Yurii S
YS
Ikram
M Arfan
MA
Breteler
Monique M
MM
van Duijn
Cornelia M
CM
Oulhaj
Abderrahim
A
Heun
Reinhard
R
Cortina-Borja
Mario
M
Morgan
Kevin
K
Robson
Kathryn
K
Smith
A David
AD
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*
D053327:Apolipoprotein E4; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D014168:Transferrin