title: Polymorphisms in cytokine and cellular adhesion molecule genes and susceptibility to hematotoxicity among workers exposed to benzene.
abstract: Benzene is a recognized hematotoxin and leukemogen but its mechanism of action and the role of genetic susceptibility are still unclear. Cytokines, chemokines, and cellular adhesion molecules are soluble proteins that play an important regulatory role in hematopoiesis. We therefore hypothesized that variation in these genes could influence benzene-induced hematotoxicity. We analyzed common, well-studied single-nucleotide polymorphisms (SNPs) in 20 candidate genes drawn from these pathways in a study of 250 workers exposed to benzene and 140 unexposed controls in China. After accounting for multiple comparisons, SNPs in five genes were associated with a statistically significant decrease in total WBC counts among exposed workers [IL-1A (-889C>T), IL-4 (-1098T>G), IL-10 (-819T>C), IL-12A (8685G>A), and VCAM1 (-1591T>C)], and one SNP [CSF3 (Ex4-165C>T)] was associated with an increase in WBC counts. The adhesion molecule VCAM1 variant was particularly noteworthy as it was associated with a decrease in B cells, natural killer cells, CD4+ T cells, and monocytes. Further, VCAM1 (-1591T>C) and CSF3 (Ex4-165C>T) were associated, respectively, with decreased (P = 0.041) and increased (P = 0.076) CFU-GEMM progenitor cell colony formation in 29 benzene-exposed workers. This is the first report to provide evidence that SNPs in genes that regulate hematopoiesis influence benzene-induced hematotoxicity.
authors.affiliation: Division of Cancer Epidemiology, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD 20892-7240, USA. qingl@mail.nih.gov
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
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: Matthew S
authors.initials: MS
authors.lastname: Forrest
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Martha
authors.initials: M
authors.lastname: Linet
authors.forename: Mustafa
authors.initials: M
authors.lastname: Dosemeci
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.forename: Rona S
authors.initials: RS
authors.lastname: Weinberg
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: Suramya
authors.initials: S
authors.lastname: Waidyanatha
authors.forename: Sungkyoon
authors.initials: S
authors.lastname: Kim
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
mesh_terms: D000328:Adult; D001554:Benzene / Q000506:poisoning*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D009784:Occupational Diseases / Q000139:chemically induced* / Q000235:genetics; D016273:Occupational Exposure; D020641:Polymorphism, Single Nucleotide
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D001554:Benzene