Association between the c. 2495 A>G ATP7B Polymorphism and Sporadic Alzheimer's Disease

Abstract

Nonceruloplasmin-bound copper ("free") is reported to be elevated in Alzheimer's disease (AD). In Wilson's disease (WD) Cu-ATPase 7B protein tightly controls free copper body levels. To explore whether the ATP7B gene harbours susceptibility loci for AD, we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WD-causing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P = .074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P = .028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.

Figure 1

Analytical procedures for ATP7B SNPs detection. (a) PCR-restriction fragment length polymorphism (RFLP) assay for detection of c.1216 T>G SNP. Lane 1 : PCR 100 bp low ladder. Lane 2 : GG genotype (375 bp and 209 bp RFLP). Lane 3 : TG genotype (584 bp, 375 bp and 209 bp RFLP). Lane 4 : TT genotype (584 bp RFLP). In the electropherogram the arrow indicates the TG genotype. (b) TaqMan allelic discrimination assays for detection of c.2495 A>G SNP. Blue: AA genotype. Green: TG genotype. Red: GG genotype; x: undetermined.

Figure 2

Pairwise LDs are shown, calculated between the ATP7B gene SNPs in AD, controls, whole sample and in HapMap European origin populations (CEU: Utah residents with Northern and Western European ancestry from the CEPH collection; TSI: Tuscans in Italy). The top panel depicts the location of the SNPs in the AT7PB gene. The intensity of the box shading is proportional to the strength of the LD (D′ confidence bounds) for the marker pair, which is also indicated as a percentage within each box.