Replication of GWAS identifies RTEL1, CDKN2A/B, and PHLDB1 SNPs as risk factors in Portuguese gliomas patients

  • Marta Viana-Pereira
  • Daniel Antunes Moreno
  • Paulo Linhares
  • Júlia Amorim
  • Rui Nabiço
  • Sandra Costa
  • Rui Vaz
  • Rui Manuel ReisEmail author
Original Article


Diffuse gliomas are the most common malignant primary brain tumors and remain incurable. A better knowledge of the tumor etiology is required. Specific single nucleotides polymorphisms (SNPs) rs4977756 (CDKN2A/B), rs6010620 (RTEL1), rs498872 (PHLDB1), rs2736100 (TERT), and rs4295627 (CCDC26) have been associated with glioma susceptibility and are potential risk biomarkers. This study aimed to analyze five SNPs associated with glioma susceptibility, in the Portuguese population. SNPs were genotyped using the Sequenom MassARRAY platform in 127 gliomas and 180 controls. Unconditional logistic regression models were used to calculate odds ratio (OR) and 95% confidence intervals. The false-positive report probability was also assessed. The associations between polymorphisms and survival were evaluated using the log-rank test. It was found that the AG and GG genotypes of the rs4977756 (CDKN2A/B) were associated with an increased risk of gliomas (OR 1.85 and OR 2.38) and glioblastomas (OR 2.77 and OR 3.94). The GA genotype of the rs6010620 (RTEL1) was associated with a decreased risk of glioblastomas (OR 0.45). We also observed that the GA genotype of the rs498872 (PHLDB1) was associated with an increased risk of gliomas (OR 2.92) and glioblastomas (OR 2.39). No significant risk associations were found for the rs2736100 (TERT) and rs4295627 (CCDC26). In addition, the genotype AA of the rs498872 (PHLDB1) was associated with poor overall survival of gliomas patients (AA vs. GA, p = 0.037). The rs6010620 (RTEL1), rs4977756 (CDKN2A/B), and rs498872 (PHLDB1) are associated with glioma risk in the Portuguese population and these data may contribute to understanding gliomas etiology.









Coiled-coil domain containing 26


Cyclin-dependent kinase inhibitor 2A/B


Confidence interval


False-positive report probability




Genome-wide association studies


Odds ratio


Overall survival


Pleckstrin Homology-Like Domain Family B member 1


Regulator of telomere elongation helicase 1


Single nucleotide polymorphisms




Telomerase reverse transcriptase


World Health Organization


Author contributions

MV-P: Genotyping of samples, analysis of polymorphisms and patient’s data, tables and figures, manuscript review; DAM: interpreted genotyping, patient’s data, bibliography review, manuscript writing; PL, JA, RN and RV: clinical data collection, interpretation and final review; SC: collections of samples, DNA extraction, genotyping; RMR: study design, scientific support, results analysis, manuscript review, research coordination.


The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by Fundacão para a Ciência e Tecnologia (FCT), Portugal (; grant PTDC/SAU-ONC/115513/2009_FCOMP-01-0124-FEDER-015949 to R.M.R.). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). M.V.P. was recipient of an FCT Post-Doctoral fellowship (ref: SFRH/BPD/104290/2014).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Institutional ethics committees of S. João and Braga Hospitals (Approval 29/10/2007).

Informed consent

Not applicable. This is a retrospective study where any information that allows participants identification is not disclosed.


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.School of Medicine, Life and Health Sciences Research Institute (ICVS)University of MinhoBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryMinhoPortugal
  3. 3.Barretos Cancer HospitalMolecular Oncology Research CenterBarretosBrazil
  4. 4.Department of NeurosurgeryHospital S. JoãoPortoPortugal
  5. 5.Faculty of MedicineUniversity of PortoPortoPortugal
  6. 6.Department of OncologyHospital de BragaBragaPortugal

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