Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity.
BACKGROUND
Benzene is an established human haematotoxin, with substantial interindividual variation in benzene-induced toxicity.


METHODS
To further examine if genetic variation contributes to benzene haematotoxicity, we analysed 1023 tagSNPs in 121 gene regions important for benzene metabolism, haematopoiesis, leukaemia and lymphoma among 250 workers exposed to benzene and 140 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyse the relationship between genetic polymorphisms and total white blood cell (WBC) count and its subtypes, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. The minp test assessed the association on the gene region level. The false discovery rate method was used to control for multiple comparisons.


RESULTS
VEGF (minp = 0.0030) and ERCC3 (minp = 0.0042) were the most significantly associated gene regions with altered WBC counts among benzene-exposed workers, after accounting for multiple comparisons. Highly significant changes were also found for WBC subtype counts, including granulocytes, CD4+ T cells and lymphocytes for VEGF and granulocytes and NK cells for ERCC3. Further, in workers exposed to <1 ppm, a SNP in VEGF was associated with changes in WBC and granulocyte counts, and SNPs in ERCC3 were associated with changes in WBC, NK cell and granulocyte counts.


CONCLUSIONS
Our findings suggest that genetic variation in VEGF, which plays an important role in blood vessel growth, and ERCC3, which is a member of the DNA repair pathway and is responsible for repairing bulky DNA adducts formed by chemicals, may contribute to individual susceptibility to benzene-induced haematotoxicity at relatively low levels of benzene exposure.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-7240, USA. hosgoodd@mail.nih.gov
H D
HD
Hosgood
L
L
Zhang
M
M
Shen
S I
SI
Berndt
R
R
Vermeulen
G
G
Li
S
S
Yin
M
M
Yeager
J
J
Yuenger
N
N
Rothman
S
S
Chanock
M
M
Smith
Q
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Lan
D001554:Benzene / Q000633:toxicity*; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006402:Hematologic Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009784:Occupational Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D016273:Occupational Exposure / Q000009:adverse effects / Q000032:analysis; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D004268:DNA-Binding Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C072022:XPBC-ERCC-3 protein; D004265:DNA Helicases; D001554:Benzene