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Funct Integr Genomics. 2019 Jan 31. doi: 10.1007/s10142-019-00658-3. [Epub ahead of print]

Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity.

Author information

1
Data Mining Division, Faculty of Automatic Control, Electronic and Computer Science, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland.
2
Cellular Biology Group, Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, OX11 0RQ, UK.
3
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, OX11 0RQ, UK.
4
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
5
Radiation Biology Section, Biomedical Physics Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
6
Department of Public Health and Institute for Molecular Medicine FIMM, University of Helsinki, 00140, Helsinki, Finland.
7
Data Mining Division, Faculty of Automatic Control, Electronic and Computer Science, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland. joanna.polanska@polsl.pl.

Abstract

Individual variability in response to radiation exposure is recognised and has often been reported as important in treatment planning. Despite many efforts to identify biomarkers allowing the identification of radiation sensitive patients, it is not yet possible to distinguish them with certainty before the beginning of the radiotherapy treatment. A comprehensive analysis of genome-wide single-nucleotide polymorphisms (SNPs) and a transcriptional response to ionising radiation exposure in twins have the potential to identify such an individual. In the present work, we investigated SNP profile and CDKN1A gene expression in blood T lymphocytes from 130 healthy Caucasians with a complex level of individual kinship (unrelated, mono- or dizygotic twins). It was found that genetic variation accounts for 66% (95% CI 37-82%) of CDKN1A transcriptional response to radiation exposure. We developed a novel integrative multi-kinship strategy allowing investigating the role of genome-wide polymorphisms in transcriptomic radiation response, and it revealed that rs205543 (ETV6 gene), rs2287505 and rs1263612 (KLF7 gene) are significantly associated with CDKN1A expression level. The functional analysis revealed that rs6974232 (RPA3 gene), involved in mismatch repair (p value = 9.68e-04) as well as in RNA repair (p value = 1.4e-03) might have an important role in that process. Two missense polymorphisms with possible deleterious effect in humans were identified: rs1133833 (AKIP1 gene) and rs17362588 (CCDC141 gene). In summary, the data presented here support the validity of this novel integrative data analysis strategy to provide insights into the identification of SNPs potentially influencing radiation sensitivity. Further investigations in radiation response research at the genomic level should be therefore continued to confirm these findings.

KEYWORDS:

CDKN1A; GWAS; Radiation response; Twin study; p value integration

PMID:
30706161
DOI:
10.1007/s10142-019-00658-3

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