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 <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.
Moslehi
Roxana
R
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Blvd., EPS 8047, Rockville, MD 20852 USA. moslehir@mail.nih.gov
Chatterjee
Nilanjan
N
Church
Timothy R
TR
Chen
Jinbo
J
Yeager
Meredith
M
Weissfeld
Joel
J
Hein
David W
DW
Hayes
Richard B
RB
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
D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human