Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.
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DOI：
10.1007/s00401-016-1533-5
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发表时间：
2016-06
影响因子：
12.7
通讯作者：
Cruchaga C
中科院分区：
文献类型：
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作者：
Piccio L;Deming Y;Del-Águila JL;Ghezzi L;Holtzman DM;Fagan AM;Fenoglio C;Galimberti D;Borroni B;Cruchaga C
TREM2 的低频编码变异与阿尔茨海默病 (AD) 风险增加相关，而该基因的功能缺失突变会导致常染色体隐性早发性痴呆，称为纳苏-哈科拉病 (NHD)。 TREM2 可作为脑脊液 (CSF) 和血浆中的可溶性蛋白被检测到，并且其 CSF 水平在炎症性中枢神经系统疾病中升高。我们测量了大型 AD 病例对照数据集 (n=180) 和 40 个 TREM2 风险变异携带者的 CSF 中的可溶性 TREM2 (sTREM2)，以确定 CSF sTREM2 水平是否与 AD 状态或突变状态相关。我们还进行了遗传学研究，以确定与 CSF sTREM2 水平相关的遗传变异。 CSF（而非血浆）sTREM2 与 CSF 总 tau 和磷酸化 tau 水平高度相关（分别为 r=0.35，p<1×10-4；r=0.40，p<1×10-4），但与 CSF Aβ42 不相关。 AD 病例的脑脊液 sTREM2 水平高于对照组（P=0.01）。 NHD 相关 TREM2 变异的携带者表现出显着较低的 CSF sTREM2 水平，支持这些突变导致蛋白质产生/功能降低的假设（R136Q、D87N、Q33X 或 T66M；p=1×10-3）。相反，与非携带者相比，R47H 携带者的 CSF sTREM2 水平显着较高 (P=6×10-3)，表明该变异不会影响蛋白质表达，并通过与 NHD 变异不同的致病机制增加 AD 风险。在 CSF sTREM2 水平的 GWAS 分析中，最显着的信号位于 MS4A 基因位点 (P=5.45×10-07)，对应于据报道与该位点中 AD 风险相关的 SNP 之一。此外，参与病毒细胞进入和囊泡运输相关途径的 SNP 比例过高，表明脑脊液 sTREM2 水平可能是 AD 的信息表型。
Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured solubleTREM2 (sTREM2) in the CSF of a large AD case-control dataset (n=180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r=0.35, p<1×10-4; r=0.40, p<1×10-4 respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P=0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; p=1×10-3). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P=6×10-3), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P=5.45×10-07) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.