Title: Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer.
Authors: Yuan, Jian-Min; Chan, Kenneth K; Coetzee, Gerhard A; Castelao, J Esteban; Watson, Mary A; Bell, Douglas A; Wang, Renwei; Yu, Mimi C
Published In Carcinogenesis, (2008 Jul)
Abstract: 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.
PubMed ID: 18544563
MeSH Terms: Adult; Arylamine N-Acetyltransferase/genetics; Arylamine N-Acetyltransferase/metabolism; Carcinogens/metabolism*; Carcinoma, Transitional Cell/chemically induced; Carcinoma, Transitional Cell/enzymology; Carcinoma, Transitional Cell/genetics; Case-Control Studies; Cytochrome P-450 CYP1A2/genetics; Cytochrome P-450 CYP1A2/metabolism; Female; Genetic Predisposition to Disease; Glutathione Transferase/genetics; Glutathione Transferase/metabolism; Humans; Isoenzymes/genetics; Isoenzymes/metabolism; Male; Middle Aged; Urinary Bladder Neoplasms/chemically induced; Urinary Bladder Neoplasms/enzymology*; Urinary Bladder Neoplasms/genetics*; Urinary Bladder/drug effects; Urinary Bladder/enzymology