title: Association of K832R and R952K SNPs of Wilson's disease gene with Alzheimer's disease.
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.
authors.affiliation: Department of Neurology, Campus Bio-Medico University, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bucossi
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.forename: Stefania
authors.initials: S
authors.lastname: Mariani
authors.forename: Mariacarla
authors.initials: M
authors.lastname: Ventriglia
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.forename: Simone
authors.initials: S
authors.lastname: Migliore
authors.forename: Dario
authors.initials: D
authors.lastname: Manfellotto
authors.forename: Carlo
authors.initials: C
authors.lastname: Salustri
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vernieri
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Rossini
authors.forename: Rosanna
authors.initials: R
authors.lastname: Squitti
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001120:Arginine / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D001120:Arginine; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D008239:Lysine