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Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant

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Abstract

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.

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Abbreviations

MAPKAP1:

Mitogen-activated protein kinase-associated protein 1

MTOR:

Mechanistic target of rapamycin

GWAS:

Genome-wide association study

MTORC2:

MTOR complex 2

CHS:

Southern Han Chinese

MAF:

Minor allelic frequency

LD:

Linkage disequilibrium

EMSA:

Electrophoretic mobility-shift assay

ChIP:

Chromatin immunoprecipitation assay

OR:

Odds ratio

CI:

Confidence interval

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Funding

This work was funded by National Natural Science Foundation, P.R.C (Grant Number 81301772); Joint Funds for the Innovation of Science and Technology of Fujian province, P.R.C (Grant Number 2016Y9016); Natural Science Foundation of Fujian Province, P.R.C (Grant Number 2014J05087); and Startup Fund for Scientific Research of Fujian Medical University (Grant Number 2017XQ1085).

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Authors and Affiliations

  1. Department of Medical Oncology (39th Section), The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Liming Huang, Xin You, Xi Shi, Shu Zhang & Hualan Hong

  2. Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Wenshen Xu

  3. Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, China

    Danfang Yan

  4. Department of Medicine, The Third Affiliated People’s Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China

    Lian Dai

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  1. Liming Huang
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  2. Wenshen Xu
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  3. Danfang Yan
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  4. Xin You
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  5. Xi Shi
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  6. Shu Zhang
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  7. Hualan Hong
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  8. Lian Dai
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Contributions

LMH, WSX, DFY, XY, XS, SZ, HLH and LD participated in the study design. LMH, WSX, DFY, XY, SZ, HLH and LD performed the experiment. LMH, WSX, DFY, XY, XS, SZ and LD were involved in data collection and data interpretation. LMH, WSX, DFY, XY and LD participated in the statistical analyses. LMH and LD wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Liming Huang or Lian Dai.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Huang, L., Xu, W., Yan, D. et al. Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant. Cell Mol Neurobiol 40, 643–652 (2020). https://doi.org/10.1007/s10571-019-00763-8

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  • DOI: https://doi.org/10.1007/s10571-019-00763-8

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