Laws Simon M, Perneczky Robert, Wagenpfeil Stefan, Müller Ulrich, Förstl Hans, Martins Ralph N, Kurz Alexander, Riemenschneider Matthias
Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Australia.
Hum Mutat. 2005 Jul;26(1):29-35. doi: 10.1002/humu.20180.
Alzheimer disease (AD), vascular dementia, and stroke are all associated with inflammation though their respective initiating factors differ. Recently a polymorphism in the proinflammatory cytokine tumor necrosis factor (TNF), in association with apolipoprotein E (APOE), was reported to increase AD risk. Two SNPs, rs1799724 (-850C>T; NT_007592.14:g.22400733C>T) and rs1800629 (-308G>A; [NT_007592.14:g.22401282G>A]), and the APOE polymorphism were genotyped in 506 patients with sporadic AD and in 277 cognitively healthy controls. In a subset of 90 individuals we also investigated whether these SNPs exerted any functional effects on cerebrospinal fluid (CSF) beta-amyloid (Abeta) levels. The frequency of the rs1799724 genotypes and the rs1799724-T allele were significantly different in AD individuals (P=0.009; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.13-2.34), while the rs1800629 SNP was not associated with AD. Significant interaction was observed between the rs1799724-T and APOE epsilon4 alleles in that the rs1799724-T allele significantly modified risk associated with possession of the epsilon4 allele only (epsilon4 in absence of rs1799724-T: OR, 2.92; 95% CI, 2.00-4.27; epsilon4 in presence of rs1799724-T: OR, 6.65; 95% CI, 3.26-13.55; P=0.03). Haplotyping analysis revealed a significant overrepresentation of an rs1799724-T/rs1800629-G haplotype in AD (P=0.012; OR, 1.60; 95% CI, 1.11-2.29), although to a lesser degree than rs1799724-T alone. Further, the rs1799724-T allele was found to be associated with lower levels of CSF Abeta42 (P=0.023), thus corroborating the genetic findings. Inheritance of the rs1799724-T allele appears to synergistically increase the risk of AD in APOEepsilon4 carriers and is associated with altered CSF Abeta42 levels. Further investigations are warranted to assess the significance of these novel findings.
阿尔茨海默病（AD）、血管性痴呆和中风都与炎症相关，尽管它们各自的起始因素有所不同。最近有报道称，促炎细胞因子肿瘤坏死因子（TNF）的一种多态性与载脂蛋白E（APOE）相关，会增加患AD的风险。对506例散发性AD患者和277名认知健康对照者进行了两个单核苷酸多态性（SNP），即rs1799724（-850C>T；NT_007592.14:g.22400733C>T）和rs1800629（-308G>A；[NT_007592.14:g.22401282G>A]）以及APOE多态性的基因分型。在90名个体的亚组中，我们还研究了这些SNP是否对脑脊液（CSF）β淀粉样蛋白（Aβ）水平产生任何功能影响。rs1799724基因型和rs1799724 - T等位基因在AD个体中的频率有显著差异（P = 0.009；优势比[OR]，1.63；95%置信区间[CI]，1.13 - 2.34），而rs1800629 SNP与AD无关。在rs1799724 - T和APOE ε4等位基因之间观察到显著的相互作用，即rs1799724 - T等位基因仅显著改变了与携带ε4等位基因相关的风险（不存在rs1799724 - T时的ε4：OR，2.92；95% CI，2.00 - 4.27；存在rs1799724 - T时的ε4：OR，6.65；95% CI，3.26 - 13.55；P = 0.03）。单倍型分析显示，rs1799724 - T/rs1800629 - G单倍型在AD中显著过度表达（P = 0.012；OR，1.60；95% CI，1.11 - 2.29），尽管程度低于单独的rs1799724 - T。此外，发现rs1799724 - T等位基因与较低水平的CSF Aβ42相关（P = 0.023），从而证实了基因研究结果。rs1799724 - T等位基因的遗传似乎协同增加了APOEε4携带者患AD的风险，并与CSF Aβ42水平的改变有关。有必要进行进一步研究以评估这些新发现的意义。
