title: Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men.
abstract: Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-6968, USA. gbar@ucla.edu
authors.forename: George
authors.initials: G
authors.lastname: Bartzokis
authors.forename: Po H
authors.initials: PH
authors.lastname: Lu
authors.forename: Todd A
authors.initials: TA
authors.lastname: Tishler
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Peters
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kosenko
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Barrall
authors.forename: J Paul
authors.initials: JP
authors.lastname: Finn
authors.forename: Pablo
authors.initials: P
authors.lastname: Villablanca
authors.forename: Gerhard
authors.initials: G
authors.lastname: Laub
authors.forename: Lori L
authors.initials: LL
authors.lastname: Altshuler
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Jim
authors.initials: J
authors.lastname: Mintz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Neely
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D001931:Brain Mapping; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins