title: Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity.
abstract: Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4(+)-T cell, CD8(+)-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4(+)-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity.
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, MD 20892, USA. shenmi@mail.nih.gov
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Roel
authors.initials: R
authors.lastname: Vermeulen
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Rappaport
authors.forename: Weihong
authors.initials: W
authors.lastname: Guo
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Martha
authors.initials: M
authors.lastname: Linet
authors.forename: Songnian
authors.initials: S
authors.lastname: Yin
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Forrest
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000328:Adult; D001554:Benzene / Q000633:toxicity*; D001773:Blood Cells / Q000187:drug effects*; D003430:Cross-Sectional Studies; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D005090:Exodeoxyribonucleases; D005260:Female; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D001554:Benzene