ArticlesNAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses
Introduction
The inability to replicate results on many associations between common genetic polymorphisms and complex diseases has raised scepticism in this area of research.1 One of the few exceptions could be the association between the risk of bladder cancer and polymorphisms in two carcinogen-detoxification genes—NAT2 and GSTM1. However, evidence for an association relies on analyses of pooled data and meta-analyses of relatively small studies (range 23–374 patients, average about 100 per study), and concern has been raised about publication bias and heterogeneity of results.2, 3, 4, 5, 6, 7, 8, 9 Tobacco smoking is an important cause of bladder cancer,10 and previous analyses have suggested that the relative risk from smoking is stronger for NAT2 slow acetylators than for rapid or intermediate acetylators.2, 5, 11 This interaction is biologically plausible, since aromatic amines, which are thought to be the most important class of bladder carcinogens in tobacco smoke,12 are detoxified by NAT2.13 However, epidemiological evidence for this interaction is even weaker than for the overall genotype association. Associations between bladder-cancer risk and polymorphisms in other carcinogen-detoxification genes such as NAT1 and other glutathione-S-transferases have been less frequently explored, with inconsistent results across studies.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35
We report results on the associations of polymorphisms in NAT and GST genes with bladder-cancer risk and their interaction with cigarette smoking among participants in the Spanish Bladder Cancer Study. This study was designed to have adequate statistical power for rigorous evaluation of the proposed associations between genetic variation in NAT2 and GSTM1 and bladder-cancer risk. We also report meta-analyses of NAT2, GSTM1, smoking, and bladder cancer that include more than twice as many patients as in previous reports.
Section snippets
Study population
The Spanish Bladder Cancer Study is a hospital-based case-control study based in 18 hospitals in five areas in Spain (Asturias, Barcelona metropolitan area, Vallès/Bages, Alicante, and Tenerife). Eligible “cases” were aged 21–80 years and had newly diagnosed, histologically confirmed carcinoma of the urinary bladder in 1998–2001. Diagnostic slides from each patient were reviewed by a panel of expert pathologists to confirm the diagnosis and to ensure uniformity of classification criteria, based
Results
The study population was white, predominantly male, and a high proportion were smokers, mostly of black tobacco (table 1). In this population, NAT2 slow-acetylator and GSTM1 null (−/−) genotypes significantly increased the risk of bladder cancer (table 2). The risk of bladder cancer was 40% higher in NAT2 slow acetylators than in NAT2 rapid or intermediate acetylators (odds ratio 1·4 [95% CI 1·2–1·7]); NAT2 rapid acetylators and intermediate acetylators had similar risks of bladder cancer (
Discussion
This report provides compelling evidence of an increased bladder-cancer risk associated with the GSTM1 null and NAT2 slow-acetylation genotypes. The latter association was particularly important among cigarette smokers. Although the relative risks for polymorphisms in NAT2 and GSTM1 genes are modest, these polymorphisms could account for a large proportion of bladder cancers because they are very common in the population. From our data, we estimate that these polymorphisms cause 31% (95% CI
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