Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: Significantly reduced risk in subjects with NAT1*10

The role of hereditary polymorphisms of the arylamine N-acetyltransferase 1 (NAT1) gene in the etiology of urinary bladder cancer is controversial. NA T1 is expressed in the urothelium and may O-acetylate hydroxyl amines, part icularly in subjects with low NAT2 activity. Thus, NAT1 polymorphisms may a ffect the individual bladder cancer risk by interacting with environmental factors (smoking and occupational risks) and by interacting with the NAT2 g ene. We studied the frequencies of the NAT1 haplotypes *3, *4, *10, *11, *1 4, *15, *17, and *22 in 425 German bladder cancer patients and 343 controls by PCR-RFLP. NAT1*10 allelic frequency was lower in bladder cancer patient s (15.1%) compared with controls (20.4%; P = 0.012). Genotypes that include d NAT1*10 were significantly less frequent among the cases (odds ratio adju sted for age, gender, and smoking, 0.65; 95% confidence interval, 0.46-0.91 ; P = 0.013). Two subtypes of NAT1*11 were detected: *11A (-344T, -40T, 445 A, 459A, 640G, and 1095A) and *11C (-344T, -40T, 459A, 640G, and 1095A). Th e allele frequency of NAT1*11 was 4.3% in the cases versus 3.9% in the cont rols. The rare low-active NAT1*14A was overrepresented in the cases (P = 0. 026). With regard to the NAT2 genotype, our data showed: (a) a partial link age of NAT1*10 to NAT2*4; (b) a clear underrepresentation of NAT1*10 genoty pes among rapid NAT2 genotypes in the cases studied (odds ratio, 0.39; 95% confidence interval, 0.22-0.68; P = 0.001), and (c) a gene-gene-environment interaction. NAT2*'slow/NAT1*4 genotype combinations with a history of occ upational exposure were 5.96 (2.96-12.0) times more frequent in cancer case s than in controls without risk occupation (P < 0.0001). Hence, our data su ggest that individuals provided with NAT2*4 and NAT1*10 are at a significan tly lower risk for bladder cancer, particularly when exposed to environment al risk factors.