title: Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.
abstract: Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case-control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR=0.83, 95% CI: 0.71-0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin (TF; GeneID: 7018). Additionally, we observed a suggestive protective association (OR=0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 (TFR2; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1, CYB561, or HFE. Taken together with previous findings in model systems, our results suggest that TF or a TF-TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.
authors.affiliation: Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA. Electronic address: shannon.rhodes@ucla.edu.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, 300 Herston Rd, Brisbane, QLD 4006, Australia; University of Queensland, School of Medicine, Brisbane, Australia; Princess Alexandra Hospital, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Centre for Research in Epidemiology and Population Health, Biostatistics team, INSERM U1018, F-94276 le Kremlin Bicêtre, France; Univ Paris-Sud, UMRS 1018, F-94276 le Kremlin Bicêtre, France.
authors.forename: Ismaïl
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 West Carson, Bldg E5, Torrance, CA 90502, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, INSERM UMR-S 775, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA; Department of Biomathematics, David Geffen School of Medicine at UCLA, Box 951766, Room 5303 Life Sciences, Los Angeles, CA 90095-1766, USA; Department of Biostatistics, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Bronstein
authors.affiliation: Centre for Research in Epidemiology and Population Health, Social and Occupational Determinants of Health, INSERM U1018, F-94807 Villejuif, France; Univ Versailles St-Quentin, UMRS 1018, F-94807, Villejuif France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Elbaz
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan 4111, Brisbane, Australia; Department of Neurology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 West Carson, Bldg E5, Torrance, CA 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA; Department of Environmental Health Sciences, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA.
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011990:Receptors, Transferrin / Q000235:genetics; D014168:Transferrin / Q000235:genetics*; D055815:Young Adult
chemical_list: D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; D007501:Iron
keywords: Epidemiology; Genetics; Iron homeostasis; Pooled-analysis; Transferrin; Transferrin receptor 2