NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses

Abstract

Background: Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent.

Methods: We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports.

Findings: In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86).

Interpretation: The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer.

Relevance to practice: Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.

Figure 1

Association between increasing smoking intensity (average number of cigarettes per day in categories of 10 cigarettes) and bladder cancer risk compared to never smokers, stratified by NAT2 acetylation genotype. Odds ratios are from conventional logistic regression models adjusted for age, gender, region, smoking duration (< 20 years, 20-<30 years, 30-<40 years, 40-<50 years, ≥ 50 years) and smoking cessation (current/former smokers). Error bars represent 95% confidence intervals.

Figure 2

Meta-analysis of studies of NAT2 slow acetylation genotype and bladder cancer risk (A) and case-only meta-analysis of studies of NAT2 slow acetylation gentype, cigarette smoking and bladder cancer. The horizontal axis plots odds ratios and 95% CI on a logarithmic scale. The size of black circles are proportional to the study size for studies with 50 or more cases, Disagreements between the number of cases for the same study in panels A and B are due to cases with missing smoking information.

Figure 3

Meta-analysis of studies of GSTM1 null genotype and bladder cancer risk (A) and case-only meta-analysis of studies of GSTM1 null genotype, cigarette smoking and bladder cancer. The horizontal axis plots odds ratios and 95% CI on a logarithmic scale. The size of black circles are proportional to the study size for studies with 50 or more cases, Disagreements between the number of cases for the same study in panels A and B are due to cases with missing smoking information.