Differential interactions between GSTM1 and NAT2 genotypes on aromatic DNAadduct level and HPRT mutant frequency in lung cancer patients and population controls

We have studied the influence of GSTM1 and NAT2 genotypes on aromatic DNA a dduct level (AL) and HPRT mutant frequency (MF) in smokers with newly diagn osed lung cancer and matched population controls. AL was analyzed in relati on to genotypes in 170 cases and 144 controls (113 current/recent smokers a nd 201 former/never smokers), and MF in 157 cases and 152 controls (155 eve r smokers and 154 never smokers). Both genotypes exhibited the a priori exp ected effects on AL and MF among controls only, especially among smoking co ntrols [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 smoki ng controls, the NAT2 slow genotype [odds ratio (OR), 7.5; 95% confidence i nterval (CI), 1.5-38.4], in particular in combination with the GSTM1 null g enotype (OR, 19.3, 95% CI, 1.1-338.6 for null/slow versus positive/rapid) w as strongly associated with high AL. The null/slow combination was also sig nificantly associated with high MF among ever smokers (cases and controls p ooled) with lower pack-years (OR, 3.7; 95% CI, 1.3-10.7 versus all of the o ther genotypes; OR, 5.1; 95% CI, 1.2-22.4 versus positive/rapid). In contra st, an antagonistic gene-gene interaction was seen among smoking cases for both AL and MF. Only currently smoking cases with the combined GSTM1 null a nd NAT2 rapid genotype showed a positive correlation between InAL and InMF (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 e ver-smoking cases diagnosed at higher pack-years, whereas the slow genotype was associated with high MF at lower pack-years. These findings suggest th at the influence of NAT2 genotype on AL and MF and its interaction with GST M1 genotype may be dose dependent. The NAT2 slow genotype, in particular wh en combined with the GSTM1 null genotype, may confer increased susceptibili ty to adduct formation, gene mutation, and lung cancer when the smoking dos e is low.