Individual DNA repair capacity is modulated by the genetic background to which hundreds of single nucleotide polymorphisms (SNPs) or haplotype combinations in DNA repair genes are likely to contribute. A large number of studies have been published on the association between DNA repair gene polymorphisms and cancer risk, whereas only few small studies investigated the relation between DNA repair phenotypic assays and cancer risk or DNA repair polymorphisms. In order to identify functional SNPs/haplotypes modulating DNA repair phenotypes and to investigate their potential impact on cancer risk, we have performed a genotype-phenotype correlation study evaluating levels of DNA damage and DNA repair capacity in blood cells treated at low doses of different DNA damaging agents. We investigated the association between genotypes/haplotypes and the DNA repair capacity measured with the following DNA repair phenotypic assays on cryopreserved lymphocytes from 225 healthy individuals: Comet assay after treatment with BPDE, phosphorylation of histone H2AX after treatment with γ-rays, OGG1 glycosylase activity, OGG1 and ERCC1 expression levels. Sixty-five DNA repair genes and a total of 768 SNPs have been selected and analysed on the 225 DNA samples by using a custom GoldenGate SNP chip (Illumina). Genotype-phenotype correlation analysis identified some new possible functional variants and haplotypes. We also tested gene-gene interactions, comparing results with existing prior knowledge from different publicly available databases and crossing functional evidence with information on gene expression levels and protein-protein interaction. A confirmation of some already described interplays between different DNA repair pathways have been obtained from SNP analysis and a suggestion of new possible cross-talks have been identified that need further experimental validation. Our results can contribute to identify subjects carrying combinations of less efficient DNA repair variants/haplotypes possibly at increased cancer risk or who can better benefit from anti-cancer therapies.
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