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Polymorphisms in Cytokine and Cellular Adhesion Molecule Genes and Susceptibility to Hematotoxicity among Workers Exposed to Benzene

¹ Division of Cancer Epidemiology and Genetics and ² Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland; ³ School of Public Health, University of California, Berkeley, California; ⁴ Chinese Center for Disease Control and Prevention, Beijing, China; ⁵ School of Public Health, University of North Carolina, Chapel Hill, North Carolina; and ⁶ New York Blood Center, Clinical Services, White Plains, New York

Requests for reprints: Qing Lan, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, MSC 7240, 6120 Executive Boulevard, EPS 8109, Bethesda, MD 20892-7240. Phone: 301-435-4706; Fax: 301-402-1819; E-mail: qingl{at}mail.nih.gov.

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.

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