Department of Neurology, Campus Bio-Medico University, Rome, Italy.
J Alzheimers Dis. 2012;29(4):913-9. doi: 10.3233/JAD-2012-111997.
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.
铜稳态似乎在阿尔茨海默病（AD）患者中异常。本研究旨在评估 AD 的易感性基因是否位于威尔逊病（WD）ATP7B 基因中。我们研究了 WD 基因的单核苷酸多态性（SNP）K832R（c.2495 A>G，rs1061472）和 R952K（c.2855 G>A，rs732774）在 251 名 AD 患者和 201 名健康对照中的位置。我们还评估了它们与载脂蛋白 E（ApoE）ε4 等位基因频率的关系。K832R 中的 R 等位基因[调整后的优势比（OR）=1.71（1.12-2.60）；p=0.012]和 R952K 中的 K 等位基因[调整后的 OR=1.82（1.19-2.80）；p=0.006]ATP7B SNP 与 AD 发病风险增加相关，并且包含 2 个风险等位基因的 R832/K952 单倍型也与 AD 相关（X2=4.85；p=0.028）。相反，K832/R952 单倍型似乎对该疾病具有保护作用（X2=7.21；p=0.007）。在携带和不携带 ApoE ε4 变体的 ATP7B 等位基因频率之间没有发现差异。连锁不平衡（LD）分析显示，AD 患者（D'=0.79）和对照组（D'=0.81）中 K832R 和 R952K 取代之间存在关联。在所有 HapMap 人群中也证实了 K832R 与 R952K 之间的高度 LD。我们的研究表明，WD ATP7B 基因中存在 AD 的易感基因，这支持了铜功能障碍在导致 AD 的神经退行性过程中发挥作用或加速该过程。
