Neurology Service and CIBERNED, Marqués de Valdecilla University Hospital, University of Cantabria and IFIMAV, Santander, Spain.
J Alzheimers Dis. 2011;27(2):291-7. doi: 10.3233/JAD-2011-110794.
Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).
在阿尔茨海默病（AD）患者大脑中，tau 异常过度磷酸化和神经原纤维缠结的形成是 tau 激酶上调的结果。在一组 729 名西班牙迟发性 AD 患者和 670 名健康对照者中，我们研究了一组涉及 AD 相关部位 tau 磷酸化的 20 个候选激酶基因（PRKACB；CAMK2A；MARK1、2、3 和 4；CSNK1D；CDC2；RPS6KB1 和 2；p38α 和β；IB1；JNK1、2 和 3；MEK1 和 2；ERK1 和 2）中的变异，以解决可能影响 AD 风险和发病年龄的遗传变异假设。与对照组（39%）相比，患者（50%）中 RPS6KB2（内含子 2，rs917570）的次要等位基因频率增加（OR=1.52；95%CI1.30-1.77；p=1.24×10-5 校正后的 Bonferroni），并且当与非次要等位基因携带者的 AD 发病年龄（平均年龄 71.1 岁）相比时，这种次要等位基因的存在与 AD 发病年龄晚 3 年（平均年龄 74.1 岁）显著相关（p=4.2×10-5）。在 APOE 非 ε4 等位基因携带者中，来自 CDC2、RPS6KB1 和 2、p38α、JNK（1、2 和 3）、MEK2 和 ERK2 基因的与 AD 相关的风险等位基因的联合效应与晚发性（>76 岁）AD 显著相关（p=0.002）。来自内含子 3（rs2448347）、5（rs2456772）和 7（rs1871447）的 SNPs 的 CDC2AGC 单倍型在 APOE 非 ε4 等位基因携带者中表现出对 AD 的保护作用（置换检验 p=1.0×10-4），病例中的频率为 9%，对照组为 15%。tau 激酶途径中的常见遗传变异不仅导致 AD 易感性的个体差异，而且导致疾病表型（发病年龄）的个体差异。
