Illumina® - based multiplexed genotyping indicates a role for altered DNA repair and genomic maintenance in susceptibility to benzene toxicity

2032

Background: Benzene is a human hematotoxin and leukemogen, with a complex mechanism of action. High throughput genotyping of single nucleotide polymorphisms (SNPs) with an Oligo Pool (OPA) by Illumina® can analyze a large number of SNPs potentially related to benzene hematotoxicity. Methods: We studied 1,442 SNPs (51% intronic, 32% exonic, 12% in promoter regions, and 5% in serine, threonine, and proline (STP) regions) in 413 genes involved in metabolism, DNA repair, cell cycle control and other pathways in an OPA based on previously sequenced candidate genes in the SNP500Cancer project (<http://snp500cancer.nci.nih.gov>). We examined the association of these SNPs with benzene hematotoxicity in 242 workers exposed to benzene and 122 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyze the relationship between genetic polymorphisms and total White Blood Cell (WBC) count, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. Interaction was tested by adding a multiplicative term between the SNP (variant carriers vs. wild genotype carriers) and benzene exposure (yes/no) into a model with all subjects. The Benjamini-Hochberg False Discovery Rate (FDR) method was used to control for multiple comparisons. Results: One or more SNPs in 15 genes were associated with altered WBC counts among workers exposed to benzene (FDR adjusted p values < 0.05). We have previously reported significant associations for SNPs in 6 of these genes (MPO, IL1A, CSF3, IL10, WRN, and TP53). Here, we report that SNPs in APOB, GPX3, BLM, RAD51, and FLJ10385 (a gene in close proximity to TP53) were associated with decreased WBC counts and SNPs in IGF2R, GSK3B, RXRA, and EFNB3 were associated with increased counts. Further, the APOB (rs3791981), GPX3 (rs8177426), BLM (rs2270132), and RAD51 (rs4924496) variants affected granulocytes, lymphocytes, and some lymphocyte subsets. Tests for interaction (i.e., effect among benzene-exposed workers vs. controls) were significant for GPX3 (rs8177426; rs869975), BLM (rs2270132), RAD51 (rs4924496), GSK3B (rs1719888), and EFNB3 (rs3744262). Conclusions: Our findings suggest that SNPs in genes that play a critical role in DNA repair and genomic maintenance (i.e., WRN, TP53, BLM, and RAD51) could modify the effect of benzene on hematopoiesis.