Association of K832R and R952K SNPs of Wilson's Disease Gene with Alzheimer's Disease

Article type: Research Article

Authors: Bucossi, Serena^{a; b; 1} | Polimanti, Renato^{c; 1} | Mariani, Stefania^{a; b} | Ventriglia, Mariacarla^{a; b} | Bonvicini, Cristian^d | Migliore, Simone^b | Manfellotto, Dario^e | Salustri, Carlo^f | Vernieri, Fabrizio^a | Rossini, Paolo M.^{g; h} | Squitti, Rosanna^{a; b; *}

Affiliations: [a] Department of Neurology, “Campus Bio-Medico” University, Rome, Italy | [b] Department of Neuroscience, AFaR – Fatebenefratelli Hospital, Rome, Italy | [c] Department of Biology, “Tor Vergata” University, Rome, Italy | [d] Genetics Unit, I.R.C.C.S. Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy | [e] Clinical Physiopathology Center, AFaR – Fatebenefratelli Hospital, Rome, Italy | [f] Institute of Cognition Sciences and Technologies (CNR), Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy | [g] Department of Imaging, San Raffaele Cassino, Cassino (FR), Italy | [h] Institute of Neurology, Catholic University, Rome, Italy

Correspondence: [*] Correspondence to: Rosanna Squitti, PhD, Department of Neuroscience, AFaR – Ospedale Fatebenefratelli, 00186, Rome, Italy. Tel.: +39 06 6837 385; Fax: +39 06 6837 300; E-mail: rosanna.squitti@afar.it.

Note: [1] These authors contributed equally to the manuscript.

Abstract: Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12–2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19–2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD.

Keywords: Alzheimer's disease, ATP7B, copper, genetic association study, genetics, Wilson's disease

DOI: 10.3233/JAD-2012-111997

Journal: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 913-919, 2012