Differential Interactions between GSTM1 and NAT2 Genotypes on Aromatic DNA Adduct Level and HPRT Mutant Frequency in Lung Cancer Patients and Population Controls1
- Environmental Medicine Unit (S-M. H., S. F., B. L.) and Molecular Epidemiology Unit (K. Y., K. H.), Department of Biosciences, The Karolinska Institute, S-141 57 Huddinge Sweden, and Division of Environmental Epidemiology (F. N., G. P.), Institute of Environmental Medicine at the Karolinska Institute, S-171 77 Stockholm, Sweden
Abstract
We have studied the influence of GSTM1 and NAT2 genotypes on aromatic DNA adduct level (AL) and HPRT mutant frequency (MF) in smokers with newly diagnosed lung cancer and matched population controls. AL was analyzed in relation to genotypes in 170 cases and 144 controls (113 current/recent smokers and 201 former/never smokers), and MF in 157 cases and 152 controls (155 ever smokers and 154 never smokers). Both genotypes exhibited the a priori expected effects on AL and MF among controls only, especially among smoking controls[ significantly lower pack-years (a pack-year is defined as 1 pack of cigarettes/day for 1 year) than among cases]. Among the 42 currently smoking controls, the NAT2 slow genotype [odds ratio (OR), 7.5; 95% confidence interval (CI), 1.5–38.4], in particular in combination with the GSTM1 null genotype (OR, 19.3, 95% CI, 1.1–338.6 for null/slow versus positive/rapid) was strongly associated with high AL. The null/slow combination was also significantly associated with high MF among ever smokers (cases and controls pooled) with lower pack-years (OR, 3.7; 95% CI, 1.3–10.7 versus all of the other genotypes; OR, 5.1; 95% CI, 1.2–22.4 versus positive/rapid). In contrast, an antagonistic gene-gene interaction was seen among smoking cases for both AL and MF. Only currently smoking cases with the combined GSTM1 null and NAT2 rapid genotype showed a positive correlation between lnAL and lnMF (r, 0.64; P = 0.1), and an increase of AL with both age and daily cigarette use. This genotype combination was also associated with high MF among ever-smoking cases (OR, 4.0; 95% CI, 0.9–17.7 versus positive/rapid). There was a significant interaction between NAT2 genotype and pack-years of smoking among cases, so that the rapid genotype was associated with high MF among ever-smoking cases diagnosed at higher pack-years, whereas the slow genotype was associated with high MF at lower pack-years. These findings suggest that the influence of NAT2 genotype on AL and MF and its interaction with GSTM1 genotype may be dose dependent. The NAT2 slow genotype, in particular when combined with the GSTM1 null genotype, may confer increased susceptibility to adduct formation, gene mutation, and lung cancer when the smoking dose is low.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by the Swedish Cancer Society.
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↵2 To whom requests for reprints should be addressed, at Environmental Medicine Unit, The Karolinska Institute, CNT/NOVUM, S-141 57 Huddinge Sweden.
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↵3 The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; ETS, environmental tobacco smoke; GSTM1, glutathione S-transferase M1; NAT2, N-acetyl transferase 2; HPRT, hypoxanthine-guanine phosphoribosyl transferase; MF, mutant frequency; AL, adduct level, OR, odds ratio; CI, confidence interval; PY, pack-year (1 pack of cigarettes/day for 1 year).
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- Accepted November 29, 1900.
- Received June 6, 1900.
- Revision received October 24, 1900.
