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Cigarette Smoking, N-Acetyltransferase 2 Acetylation Status, and Bladder Cancer Risk: A Case-Series Meta-analysis of a Gene-Environment Interaction

Divisions of Cancer Prevention [P. M. M.] and Cancer Epidemiology and Genetics [R. B. H., M. G-C., N. E. C., N. R.]; National Cancer Institute, Bethesda, Maryland 20892; Department of Environmental and Occupational Medicine, University of Aarhus, Aarhus, Denmark DK-8000 [H. A., H. O.]; Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [R. A. B., M. R.]; Department of Clinical Pharmacology of the Charité 74, Humboldt University, Berlin D-10098 Germany [J .B., I. R.]; Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Kumamoto 862-0973 Japan [T. I.]; Department of Toxicology, Gazi University, Ankara 06100 Turkey [A. E. K.]; Hospital Clinico De San Carlos, Departamento de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain [J. M. L.]; Surgical Department, Urologic Unit, Randers Hospital, Randers DK-8900 Denmark [S. M.]; and Unit of Cancer Epidemiology, University of Turin, 10126 Turin, Italy [P. V.]

Tobacco use is an established cause of bladder cancer. The ability to detoxify aromatic amines, which are present in tobacco and are potent bladder carcinogens, is compromised in persons with the N-acetyltransferase 2 slow acetylation polymorphism. The relationship of cigarette smoking with bladder cancer risk therefore has been hypothesized to be stronger among slow acetylators. The few studies to formally explore such a possibility have produced inconsistent results, however. To assess this potential gene-environment interaction in as many bladder cancer studies as possible and to summarize results, we conducted a meta-analysis using data from 16 bladder cancer studies conducted in the general population (n = 1999 cases). Most had been conducted in European countries. Because control subjects were unavailable for a number of these studies, we used a case-series design, which can be used to assess multiplicative gene-environment interaction without inclusion of control subjects. A case-series interaction odds ratio (OR) >1.0 indicates that the relationship of cigarette smoking and bladder cancer risk is stronger among slow acetylators as compared with rapid acetylators. We observed an interaction between smoking and N-acetyltransferase 2 slow acetylation (OR, 1.3; 95% confidence interval, 1.0–1.6) that was somewhat stronger when analyses were restricted to studies conducted in Europe (OR, 1.5; confidence interval, 1.1–1.9), a pooling that included nearly 80% of the collected data. Using the predominantly male European study population and assuming a 2.5-fold elevation in bladder cancer risk from smoking, we estimated that the population attributable risk percent was 35% for slow acetylators who had ever smoked and 13% for rapid acetylators who had ever smoked. These results suggest that the relationship of smoking and bladder cancer is stronger among slow acetylators than among rapid acetylators.

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