Mitogen-activated protein kinase-associated protein 1 (MAPKAP1) is a unique component of the mechanistic target of rapamycin (MTOR) pathway which plays a pivotal role in carcinogenesis. The role of enhancer variant in carcinogenesis receives increased attentions. However, the significance of enhancer variants of MAPKAP1 in glioma has not yet been investigated. The associations of enhancer variants of MAPKAP1 with glioma susceptibility were evaluated in a cohort of 400 glioma patients and 651 controls. The function of glioma susceptibility locus was examined by a set of biochemical assays. We found that an enhancer variant of MAPKAP1 rs473426 was associated with a significantly increased risk of glioma in a dominant manner (OR 1.53, 95% CI 1.13-2.06; P = 0.006). The association for rs1339499 located in the same enhancer approached the borderline of significance after multiple testing correction (OR 0.74, 95% CI 0.56-0.98; P = 0.037). Furthermore, cumulative associations of rs473426 and rs1339499 with glioma risk were observed (P = 0.011). Functional analyses showed that the risk allele rs473426 C downregulated the regulatory activity of enhancer by reducing the binding affinity of a transcriptional activator NFΙC, which resulted in lower gene expression both in vitro and in vivo. These results demonstrate for the first time that enhancer variant of MAPKAP1 confers susceptibility to glioma by downregulation of MAPKAP1 expression, and provide further evidence highlighting MAPKAP1 as a cancer suppressor in glioma carcinogenesis.

中文翻译：

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MAPKAP1增强子变异介导的神经胶质瘤的遗传易感性。

丝裂原激活的蛋白激酶相关蛋白1（MAPKAP1）是雷帕霉素（MTOR）通路的机械靶标的独特组成部分，在致癌作用中起着关键作用。增强子变体在癌发生中的作用受到越来越多的关注。但是，尚未研究神经胶质瘤中MAPKAP1增强子变异的重要性。在400名神经胶质瘤患者和651名对照的队列中评估了MAPKAP1增强子变体与神经胶质瘤易感性的关系。胶质瘤易感性基因座的功能通过一系列生化分析进行了检查。我们发现，MAPKAP1 rs473426的增强子变异体以显着方式显着增加了胶质瘤的风险（OR 1.53，95％CI 1.13-2.06； P = 0.006）。多次测试校正后，位于同一增强子中的rs1339499的关联已接近显着性界限（OR 0.74，95％CI 0.56-0.98； P = 0.037）。此外，观察到rs473426和rs1339499与神经胶质瘤风险的累积相关性（P = 0.011）。功能分析表明，风险等位基因rs473426 C通过降低转录激活因子NF1C的结合亲和力来下调增强子的调节活性，从而导致体内外基因表达降低。这些结果首次证明，MAPKAP1的增强子变体通过下调MAPKAP1的表达赋予对神经胶质瘤的敏感性，并提供了进一步的证据，强调了MAPKAP1作为神经胶质瘤癌变的癌症抑制因子。037）。此外，观察到rs473426和rs1339499与神经胶质瘤风险的累积相关性（P = 0.011）。功能分析表明，风险等位基因rs473426 C通过降低转录激活因子NF1C的结合亲和力来下调增强子的调节活性，从而导致体内外基因表达降低。这些结果首次证明，MAPKAP1的增强子变体通过下调MAPKAP1的表达赋予对神经胶质瘤的敏感性，并提供了进一步的证据，强调了MAPKAP1作为神经胶质瘤癌变的癌症抑制因子。037）。此外，观察到rs473426和rs1339499与神经胶质瘤风险的累积相关性（P = 0.011）。功能分析表明，风险等位基因rs473426 C通过降低转录激活因子NF1C的结合亲和力来下调增强子的调节活性，从而导致体内外基因表达降低。这些结果首次证明，MAPKAP1的增强子变体通过下调MAPKAP1的表达赋予对神经胶质瘤的敏感性，并提供了进一步的证据，强调了MAPKAP1作为神经胶质瘤癌变的癌症抑制因子。功能分析表明，风险等位基因rs473426 C通过降低转录激活因子NF1C的结合亲和力来下调增强子的调节活性，从而导致体内外基因表达降低。这些结果首次证明，MAPKAP1的增强子变体通过下调MAPKAP1的表达赋予对神经胶质瘤的易感性，并提供了进一步的证据，强调了MAPKAP1作为神经胶质瘤癌变的癌症抑制因子。功能分析表明，风险等位基因rs473426 C通过降低转录激活因子NF1C的结合亲和力来下调增强子的调节活性，从而导致体内外基因表达降低。这些结果首次证明，MAPKAP1的增强子变体通过下调MAPKAP1的表达赋予对神经胶质瘤的敏感性，并提供了进一步的证据，强调了MAPKAP1作为神经胶质瘤癌变的癌症抑制因子。