Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, Washington 98108, USA.
Am J Med Genet B Neuropsychiatr Genet. 2012 Oct;159B(7):874-83. doi: 10.1002/ajmg.b.32094. Epub 2012 Aug 27.
Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
阿尔茨海默病（AD）的特征是大脑中存在淀粉样斑块，主要由淀粉样β肽（Aβ）组成，以及神经原纤维缠结，主要由tau 组成。过度磷酸化的 tau（p-tau）导致神经元损伤，与认知正常对照组相比，AD 脑脊液（CSF）中的 p-tau 和总 tau（t-tau）水平均升高。我们的假设是，CSF 中磷酸化 tau 水平与总 tau 水平的比值增加与激酶或磷酸酶基因的调节区域遗传变异相关，这些基因与 tau 的磷酸化状态有生物学关联。选择了位于 5 个激酶和 4 个磷酸酶基因的 5'和 3'区域内的 18 个单核苷酸多态性（SNP），以及 MAPT 基因调节区域内的两个 SNP 进行这项分析。研究样本包括 101 名 AD 患者和 169 名认知正常对照者。FYN 激酶基因中的 rs7768046 和 PPP2R4 磷酸酶基因中的 rs913275 均与 AD 患者的 CSF p-tau 和 t-tau 水平相关。这些 SNP 还与 AD 患者的 CSF t-tau（rs7768046）或 CSF p-tau（rs913275）与 t-tau 水平相关，与对照组相比存在差异。这些结果表明，rs7768046 和 rs913275 均以 AD 相关的方式影响 CSF tau 水平。
