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

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Zyla , J , Kabacik , S , O'Brien , G , Wakil , S , Al-Harbi , N , Kaprio , J , Badie , C , Polanska , J & Alsbeih , G 2019 , ' Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity ' , Functional & Integrative Genomics , vol. 19 , no. 4 , pp. 575-585 . https://doi.org/10.1007/s10142-019-00658-3

Title: Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity
Author: Zyla, Joanna; Kabacik, Sylwia; O'Brien, Grainne; Wakil, Salma; Al-Harbi, Najla; Kaprio, Jaakko; Badie, Christophe; Polanska, Joanna; Alsbeih, Ghazi
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
Date: 2019-07
Language: eng
Number of pages: 11
Belongs to series: Functional & Integrative Genomics
ISSN: 1438-793X
URI: http://hdl.handle.net/10138/308427
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.
Subject: Radiation response
CDKN1A
p value integration
Twin study
GWAS
DOUBLE-STRAND BREAKS
SIB-PAIR ANALYSIS
IONIZING-RADIATION
P-VALUES
ASSOCIATION
CANCER
REPAIR
IDENTIFICATION
METAANALYSIS
LYMPHOCYTES
1184 Genetics, developmental biology, physiology
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