Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study
1Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rockville, Maryland 20852, USA.
2Centre for Research in Environmental Epidemiology, Municipal Institute of Medical Research (IMIM), Barcelona, Spain.
3Department of Social Medicine, Medical School, University of Crete, Heraklion, Greece.
4Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rockville, Maryland 20852, USA.
5Hormone and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rockville, Maryland 20852, USA.
6Universidad de Oviedo, Oviedo, Spain.
7Department of Pharmacology & Toxicology, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292, USA.
8Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain.
9Consorci Hospitalari Parc Taulí, Sabadell, Spain.
10University Pompeu Fabra, Barcelona, Spain.
11Hospital General de Elche, Elche, Spain.
*Corresponding author. Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rockville, Maryland 20852, USA. E-mail: lubinj{at}mail.nih.gov
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Abstract |
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Background The N-acetyltransferase 2 (NAT2) enzyme detoxifies aromatic amines, an important class of carcinogens in tobacco smoke. Slow acetylation phenotype individuals have reduced detoxification capacity compared with those with a rapid/intermediate phenotype. Analysis of the Spanish Bladder Cancer Study found an odds ratio (OR) for slow acetylators relative to rapid/intermediate acetylators of 0.9 in never-smokers and 1.6 in ever-smokers, a 1.8-fold enhancement in smokers. Evidence indicates that acetylation is an exposure-dependent process, and thus the magnitude of the interaction may also depend on exposure level.
Methods We extend a comprehensive three-parameter linear-exponential model for the excess odds ratio (EOR) for smoking to include effects of NAT2 status, and reanalyse smoking and NAT2 status for the bladder cancer data.
Results We show that variations in smoking risk with NAT2 status result from interactions with smoking intensity (cigarettes per day) and not total pack-years of exposure. In addition, the relative increase in smoking risk in NAT2 slo acetylators increases with smoking intensity.
Conclusions Analyses reveal an enhanced effect for smoking intensity and bladder cancer in NAT2 slow acetylators which increases with intensity.
Keywords Bladder neoplasms, smoking, dose response, interaction
Accepted 23 February 2007
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