Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant

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.