Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity
- H D Hosgood III1,
- L Zhang2,
- M Shen1,
- S I Berndt1,
- R Vermeulen3,
- G Li4,
- S Yin4,
- M Yeager1,2,
- J Yuenger1,2,
- N Rothman1,
- S Chanock1,2,
- M Smith5,
- Q Lan1
- 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
- 2Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
- 3Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
- 4Chinese Center for Disease Control and Prevention, Beijing, China
- 5School of Public Health, University of California, Berkeley, California, USA
- Correspondence to H Dean Hosgood, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch, 6120 Executive Blvd, EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA;
- Accepted 27 June 2009
- Published Online First 22 September 2009
Introduction: 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.
Discussion: 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.
An additional table is published online only at http://oem.bmj.com/content/vol66/issue12
Funding This project was supported in part by the NIH intramural research program, and by NIH grants RO1ES06721, P42ES04705 and P30ES01896 (to MTS).
Competing interests M Simith has received consulting and expert testimony fees from law firms representing both plaintiffs and defendants in cases involving exposure to benzene. GL has received funds from the American Petroleum Institute for consulting on benzene-related health research.
Ethics approval This study was approved by the US National Cancer Institute’s and the China Center for Disease Control’s Institutional Review Boards.
Provenance and peer review Not commissioned; externally peer reviewed.