title: Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma.
abstract: 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 <0.001) (p-interaction = 0.02), but not among past or nonsmokers. Diplotypes most strongly associated with lower risks in smokers were NAT2*4/*5B (OR = 0.3, 95% CI: 0.1-0.8, p = 0.01) and NAT2*4/*4 (OR = 0.2, 95% CI: 0.04-0.7, p = 0.02), categorized as intermediate and rapid acetylators, respectively. One NAT1 diplotype, NAT1*4/*10 (OR = 0.5, 95% CI: 0.3-0.9, p = 0.03), was also associated with a decreased risk in smokers.
  
  
  CONCLUSIONS
  Our study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco smoking with respect to adenoma risk, providing leads for disease prevention.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Blvd., EPS 8047, Rockville, MD 20852 USA. moslehir@mail.nih.gov
authors.forename: Roxana
authors.initials: R
authors.lastname: Moslehi
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Church
authors.forename: Jinbo
authors.initials: J
authors.lastname: Chen
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Joel
authors.initials: J
authors.lastname: Weissfeld
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D014481:United States
chemical_list: D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human