N-ACETYLTRANSFERASE NAT1 AND NAT2 GENOTYPES AND LUNG-CANCER RISK

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved i n the activation/inactivation reactions of numerous xenobiotics, inclu ding tobacco-derived aromatic amine carcinogens, Several allelic varia nts of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenoype/genotype has bee n inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk wa s evaluated among 150 lung cancer patients and 172 control individuals , all French Caucasian smokers. The NAT1 alleles (3, *4, *10, *11, *1 4, and 15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymor phism methods using DNA extracted from peripheral white blood cells. G enotypes were classified according to current knowledge of the functio nal activity of the variant alleles. The NAT110 and NAT1*11 alleles w ere considered as rapid alleles, the NAT14 and the NAT1*3 as normal a lleles and NAT114 and NAT1*15 as slow-acetylation alleles. Logistic r egression analyses were performed taking into account the age, sex, sm oking and occupational exposures. A significant association was observ ed between lung cancer and NAT1 genotypes (P-homogeneity < 0.02) with a gene dose effect (P-trend < 0.01); compared with homozygous rapid ac etylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-1 9.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence i nterval 1.3-106.5) for heterozygous slow acetylators. None of the indi viduals were homozygous slow acetylators. Similar results were obtaine d whatever the adjustment considered. No significant association was f ound between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking- induced lung cancer. Pharmacogenetics 8:291-298 (C) 1998 Lippincott-Ra ven Publishers.