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The Glutathione S-Transferase-µ and - Genotypes in the Etiology of Prostate Cancer: Genotype-Environment Interactions with Smoking¹

Departments of Environmental Health Sciences [S. N. K.] and Epidemiology [S. L. R. K.], University of Michigan School of Public Health, Ann Arbor, Michigan 48109, and Departments of Biostatistics and Epidemiology [A. H. W., T. R. R.] and Urology [A. J. W., S. B. M.], and the Cancer Center [A. J. W., S. B. M., T. R. R.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021

It has been reported that individuals who express GSTT1, the gene coding for the class of the glutathione S-transferases (GSTs), have an elevated risk of prostate cancer (CaP). This result is supported by studies that show glutathione conjugation of some xenobiotics by the GSTs can produce mutagenic intermediates. However, the potential role of environmental factors in modifying the risk of CaP conferred by GSTT1 is not known. We investigated whether there was an interaction between smoking and the non-deleted genotypes of the µ (GSTM1) and (GSTT1) GST genes using a clinic-based study of 276 CaP cases and 499 controls. We observed no main effect of smoking (odds ratio, 0.95; confidence interval, 0.69–1.29) or GSTM1 (odds ratio, 1.00; confidence interval, 0.73–1.36) with CaP, but did observe a statistically significant main effect of GSTT1 with CaP (odds ratio, 1.61; confidence interval, 1.14–2.28) as reported previously. No interaction between smoking and GSTM1 was observed. A significant increase in the probability of having CaP was observed in men who were both smokers and carried a non-deleted GSTT1 genotype compared with men who had neither or only one of these risk factors (P = 0.049). Approximately 30.9% of CaP cases in this study could be attributed to the smokingxGSTT1 interaction. Whereas the mechanism of this interaction is not known, it is plausible that the metabolism of carcinogenic intermediates or the response to chronic inflammation associated with smoking may be modulated by the GSTT1 genotype and may modify CaP risk.

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