Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition
Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition
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DOI：
10.1073/pnas.0801227105
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发表时间：
2008-06-10
影响因子：
11.1
通讯作者：
Goate, Alison M.
中科院分区：
文献类型：
--
作者：
Kauwe, John S. K.;Cruchaga, Carlos;Goate, Alison M.
有大量证据表明，脑脊液 (CSF) 中 A beta 42 和 tau/ptau 水平是阿尔茨海默病 (AD) 的有希望的生物标志物。我们发现 A beta 和 tau 的 CSF 水平存在超过 10 倍的个体间差异，这表明这些生物标志物也可以有效地用作 AD 遗传研究的内表型。为了测试编码微管相关蛋白 tau (MAPT) 的基因的常见变异对影响脑脊液 tau/ptau 水平的作用，我们对 313 名个体的 21 个 MAPT 单核苷酸多态性 (SNP) 进行了基因分型，并测试了其与脑脊液 tau/ptau 水平的关联。我们鉴定了几个 SNP 的等位基因，它们与脑脊液 tau/ptau 水平升高相关。当使用 CSF A β 42 水平将样本分层为大脑中可能存在 A β 沉积和不存在 A β 沉积的样本时，仅在有 A β 沉积证据的个体中观察到这种关联。这种关联在独立的 CSF 系列中得到了复制。当在迟发性 AD 病例对照系列中评估这些 SNP 时，与较高 CSF tau/ptau 相关的等位基因与较早的发病年龄相关，但对 AD 风险没有影响。体内基因表达研究表明，这些等位基因与有脑 Aβ 沉积证据的个体 MAPT mRNA 水平升高相关。这种基于内表型的方法为基因 (MAPT SNP)-生理环境（A β 沉积）相互作用提供了证据，该相互作用使 A β 沉积后 CSF tau 发生变化，并表明这种相互作用容易导致 tau 病的发生和加速疾病进展。
There is substantial evidence that cerebrospinal fluid (CSF) levels of both A beta 42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both A beta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF A beta 42 levels were used to stratify the sample into those with and without likely A beta deposition in the brain the association was only observed in individuals with evidence of A beta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain A beta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (A beta deposition) interaction that places changes in CSF tau after A beta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.