Department of Neurology, Campus Bio-Medico University, Rome, Italy.
Rejuvenation Res. 2013 Feb;16(1):3-10. doi: 10.1089/rej.2012.1357.
Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
铜动态失衡导致不稳定的 Cu(2+)未与铜蓝蛋白结合（“游离”铜）可能会影响阿尔茨海默病（AD）的发病或进展。为了验证这一假说，我们研究了控制铜通过胆汁排泄和系统循环中游离铜浓度的基因 ATP7B。我们的研究在病例对照人群（n=515）中分析了 ATP7B 的信息单核苷酸多态性（SNP）。特别是，我们使用 HapMap 数据库评估了 ATP7B 基因的遗传结构，并进行了遗传关联研究。连锁不平衡（LD）分析表明，我们的信息 SNP 及其 LD SNP 覆盖了 ATP7B 基因序列的 96%，区分了两个“强 LD”块。第一个 LD 块包含编码跨膜和铜结合的基因区域，而第二个 LD 块编码铜结合结构域。遗传关联分析显示，在对所有研究的变异进行多重检验校正后，所有变体均具有显著结果（rs1801243，比值比[OR]=1.52，95%置信区间[CI]=1.10-2.09，p=0.010；rs2147363，OR=1.58，95% CI=1.11-2.25，p=0.010；rs1061472，OR=1.73，95% CI=1.23-2.43，p=0.002；rs732774，OR=2.31，95% CI=1.41-3.77，p<0.001），表明跨膜结构域中的 SNP 与 AD 风险的相关性可能强于铜结合结构域中的变体。我们的研究提供了新的见解，证实了 ATP7B 作为 AD 潜在遗传风险因素的作用。对 ATP7B 信息 SNP 的分析证实了我们之前关于 AD 全基因组关联研究中显著位点不存在 ATP7B 的假设，遗传关联研究表明，ATP7B 基因中的跨膜和三磷酸腺苷（ATP）结构域可能携带与 AD 风险相关的变体/单倍型。
