Cigarette smoking, N -acetyltransferase genes and the risk of advanced colorectal adenoma

Background: Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransferases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. Our interest is in the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco–colorectal tumor relationship by impacting on the metabolic activation and detoxification of tobacco smoke-derived carcinogens. Methods: In the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, we compared NAT1 and NAT2 gene variant distributions for 772 cases with left-sided advanced adenoma and 777 gender and age-matched controls. Individual NAT1 and NAT2 diplotypes were assigned and NAT2 acetylator phenotypes were derived. Results: Risks for advanced colorectal adenoma were significantly increased among recent smokers (current smokers or those who quit less than 10 years ago) (odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.7–3.1) and among those who smoked more than 20 cigarettes per day (OR = 1.7, 95% CI: 1.3–2.2), compared with nonsmokers. Risk decreased with increasing NAT2 phenotypic activity (0: slow, 1: intermediate, and 2: rapid) (OR trend: 0.8; 95% CI: 0.7–1.0, p-trend = 0.04) overall. When stratified by smoking status, significant phenotype-associated trends were observed among recent smokers (OR trend = 0.4, 95% CI: 0.3–0.7, p trend