Heritability of transcriptional response to ionizing radiation

Health risks following ionizing radiation (IR) exposure vary among individuals. Understanding the impact of genetic and environmental factors on IR sensitivity variance is fundamental in radiation oncology and radiation protection. Gene expression in response to IR has been widely studied in human blood. We analyzed blood sample-derived primary T-cell cultures from 16 monozygotic, 38 dizygotic pairs and 19 pairs of unrelated donors, to quantify the contribution of genetics to response variance, i.e., heritability in 9 previously identified radiation-responsive genes. To this aim, structural equation methodology was applied to expression data. Heritability was estimated for the best-fitted models incorporating the genetic factor. Transcriptional phenotype similarity increased with genetic relatedness. Only CCNG1 and CDKN1A had a significant heritability level, respectively 71.4 % and 74.1 % at the endogenous level. When exposed to IR, the heritability was significant for CCNG1 (69.3 %), CDKN1A (74.6 %), FDXR (73.4 %), BBC3 (81.1 %) and ATF3 (67.2 %) expression. Radiation exposure thus better revealed the genetic impact. The positive correlation between additive genetic effects at baseline and after irradiation further indicated a larger genetic effect on transcription variance for CCNG1 (rA = 0.95) and CDKN1A (rA = 0.69). Overall, the study quantified for the first time the human genetic contribution to IR transcriptional response variance which is significant, albeit gene dependent. Results highlight the complexity of genetic regulatory effects in DNA damage response and the potential of further similar studies to enhancing the understanding of individual response, including identification of radiotoxicity markers.