Cigarette smoking, N-acetyltransferase 2 acetylation status, and bladder cancer risk: A case-series meta-analysis of a gene-environment interaction

Tobacco use is an established cause of bladder cancer. The ability to detox ify aromatic amines, which are present in tobacco and are potent bladder ca rcinogens, is compromised in persons with the N-acetyltransferase 2 slow ac etylation polymorphism. The relationship of cigarette smoking with bladder cancer risk therefore has been hypothesized to be stronger among slow acety lators, The few studies to formally explore such a possibility have produce d 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 stu dies conducted in the general population (n = 1999 cases). Most had been co nducted in European countries. Because control subjects were unavailable fo r a number of these studies, we used a case-series design, which can be use d to assess multiplicative gene-environment interaction without inclusion o f control subjects. A case-series interaction odds ratio (OR) >1.0 indicate s that the relationship of cigarette smoking and bladder cancer risk is str onger among slow acetylators as compared with rapid acetylators, We observe d an interaction between smoking and N-acetyltransferase 2 slow acetylation (OR, 1.3; 95% confidence interval, 1.0-1.6) that was somewhat stronger whe n analyses were restricted to studies conducted in Europe (OR, 1.5; confide nce 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 re sults suggest that the relationship of smoking and bladder cancer is strong er among slow acetylators than among rapid acetylators.