Polymorphisms in cytokine and cellular adhesion molecule genes and susceptibility to hematotoxicity among workers exposed to benzene.
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.
Lan
Qing
Q
Division of Cancer Epidemiology, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD 20892-7240, USA. qingl@mail.nih.gov
Zhang
Luoping
L
Shen
Min
M
Smith
Martyn T
MT
Li
Guilan
G
Vermeulen
Roel
R
Rappaport
Stephen M
SM
Forrest
Matthew S
MS
Hayes
Richard B
RB
Linet
Martha
M
Dosemeci
Mustafa
M
Alter
Blanche P
BP
Weinberg
Rona S
RS
Yin
Songnian
S
Yeager
Meredith
M
Welch
Robert
R
Waidyanatha
Suramya
S
Kim
Sungkyoon
S
Chanock
Stephen
S
Rothman
Nathaniel
N
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
D015815:Cell Adhesion Molecules; D016207:Cytokines; D001554:Benzene