Polymorphisms in double strand break repair related genes influence radiosensitivity phenotype in lymphocytes from healthy individuals

• Published in: DNA repair 2016-04, Vol.40, p.27-34
• Main Authors: Mumbrekar, Kamalesh Dattaram, Goutham, Hassan Venkatesh, Vadhiraja, Bejadi Manjunath, Bola Sadashiva, Satish Rao
• Format: Article
• Language: English
• Subjects: Adult; Aged; DNA Breaks, Double-Stranded; DNA Ligase ATP - genetics; DNA repair; DNA Repair Enzymes - genetics; Double strand break; Female; Humans; Ku Autoantigen - genetics; Lymphocytes - metabolism; Lymphocytes - radiation effects; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Radiation Tolerance - genetics; Radiosensitivity; Recombinational DNA Repair; SNP; X-Rays; γ-H2AX
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2016.02.006

•Phenotype-genotype design useful in understanding the effect of genotype on phenotype•γ-H2AX foci assay can detect the minor variation in radiosensitivity•The rs2267437 in XRCC6 was associated with increased initial DSB damage•The rs1805388 in LIG4 was associated with increased radioresistance•Multiple risk alleles in DSB repair genes additively decrease the DSB repair capacity A range of individual radiosensitivity observed in humans can influence individual's susceptibility toward cancer risk and radiotherapy outcome. Therefore, it is important to measure the variation in radiosensitivity and to identify the genetic factors influencing it. By adopting a pathway specific genotype-phenotype design, we established the variability in cellular radiosensitivity by performing γ-H2AX foci assay in healthy individuals. Further, we genotyped ten selected SNPs in candidate genes XRCC3 (rs861539), XRCC4 (rs1805377), XRCC5 (rs3835), XRCC6 (rs2267437), ATM (rs3218698, rs1800057), LIG4 (rs1805388), NBN (rs1805794), RAD51 (rs1801320) and PRKDC (rs7003908), and analysed their influence on observed variation in radiosensitivity. The rs2267437 polymorphisms in XRCC6 was associated (P=0.0326) with increased DSB induction while rs1805388 in LIG4 (P=0.0240) was associated with increased radioresistance. Further, multiple risk alleles decreased the DSB repair capacity in an additive manner. Polymorphisms in candidate DSB repair genes can act individually or in combination to the efficacy of DSB repair process, resulting in variation of cellular radiosensitivity. Current study suggests that γ-H2AX assay may fulfil the role of a rapid and sensitive biomarker that can be used for epidemiological studies to measure variations in radiosensitivity. DSB repair gene polymorphisms can impact the formation and repair of DSBs. γ-H2AX foci analysis as well as DSBs repair gene polymorphisms can be used to assess cellular radiosensitivity, which will be useful in population risk assessment, disease prediction, individualization of radiotherapy and also in setting the radiation protection standards.