Carcinogenesis Advance Access originally published online on June 9, 2008
Carcinogenesis 2008 29(7):1386-1393; doi:10.1093/carcin/bgn136
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Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer
The Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
1 The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
2 USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
3 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
* To whom correspondence should be addressed. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454, USA. Tel: +1 612 625 8065; Fax: +1 612 624 0315; Email: jyuan{at}umn.edu
Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual’s susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyltransferase (NAT) 1 and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case–control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19–48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 [OR for the null genotype = 1.48, 95% confidence interval (CI) = 1.19–1.83]. When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend = 0.002). OR (95% CI) for one and two or more null/low-activity GST genotypes was 1.42 (1.12–1.81) and 1.71 (1.25–2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR = 2.03, 95% CI = 1.12–3.69, P = 0.02). The effect of NAT2 slow acetylation was even stronger in the presence of two or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype.
Abbreviations: AAMU, 5-acetylamino-6-amino-3-methyluracil; 4-ABP, 4-aminobiphenyl; CI, confidence interval; CYP, cytochrome P450; GST, glutathione S-transferase; Hb, hemoglobin; MU, methyluracil; MX, methylxanthine; NAT, N-acetyltransferase; OR, odds ratio
Received February 25, 2008; revised April 28, 2008; accepted May 30, 2008.