Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease

Article type: Research Article

Authors: Coon, Keith D.^a | Siegel, Andrew M.^a | Yee, Stephanie J.^a | Dunckley, Travis L.^a | Mueller, Claudius^{b; c} | Nagra, Rashed M.^d | Tourtellotte, Wallace W.^d | Reiman, Eric M.^{a; e; f} | Papassotiropoulos, Andreas^{a; g} | Petersen, Floyd F.^b | Stephan, Dietrich A.^{a; f; *} | Kirsch, Wolff M.^b

Affiliations: [a] Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA | [b] Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA, 92350, USA | [c] Free University of Berlin, Berlin, Germany | [d] Human Brain and Spinal Fluid Resource Center, Los Angeles, CA, 90073, USA | [e] Banner Alzheimer's Institute, Banner Good Samaritan Medical Center, Phoenix, AZ, 85006, USA | [f] The Arizona Alzheimer's Disease Consortium, Phoenix, AZ, 85006, USA | [g] Division of Psychiatry Research, University of Zurich, Zurich, Switzerland

Correspondence: [*] Corresponding author: D.A. Stephan, Director, Neurogenomics Division, TGen, The Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA. Tel.: +1 602 343 8727; Fax: +1 602 343 8448; http://www.tgen.org; E-mail: [email protected].

Abstract: The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder.

Keywords: Iron, iron regulatory protein 2, neurodegeneration, neurodegenerative disease, iron metabolism, Alzheimer's disease

DOI: 10.3233/JAD-2006-9301

Journal: Journal of Alzheimer's Disease, vol. 9, no. 3, pp. 225-233, 2006