Exploring Erythrocyte Glycophorin a Somatic Mutations and ERCC5 Genotypes in Atomic Bomb Survivors: An Association...

Individual differences in the effects of ionizing radiation on humans remain poorly understood. Although studies on atomic bomb survivors have demonstrated that the hemizygous glycophorin A (GPA) gene mutant fraction (GPA Mf) in erythrocytes increases significantly with increasing radiation dose, there are large individual differences in the GPA Mf. Persistent GPA mutations are believed to be derived from mutations in long-lived hematopoietic stem cells (HSCs), and genetic background related to DNA repair may contribute to individual differences in HSC mutational potential after radiation exposure. In this study, we investigated three single-nucleotide polymorphisms (SNPs) in ERCC5 that play an important role in nucleotide excision repair (NER) of DNA damage caused by radiation exposure and are involved in cancer susceptibility. We found that these SNPs affect the relationship between radiation exposure and GPA Mf in erythrocytes and identified a highly significant interaction between radiation dose and one SNP (rs751402), located 2 kb upstream of ERCC5 (P = 9.3 × 10-6). This suggests that the radiation dose response of GPA Mf is partly influenced by the genotype of ERCC5. Furthermore, the slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima survivors whose rs751402 genotype was the major homozygote. These findings suggest that ERCC5 may play a crucial role in the individual differences observed in HSC somatic gene mutability, as well as in cancer susceptibility after radiation exposure.