Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer.
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.
The Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. jyuan@umn.edu
Jian-Min
JM
Yuan
Kenneth K
KK
Chan
Gerhard A
GA
Coetzee
J Esteban
JE
Castelao
Mary A
MA
Watson
Douglas A
DA
Bell
Renwei
R
Wang
Mimi C
MC
Yu
D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D016022:Case-Control Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*
D001191:Arylamine N-Acetyltransferase; D002273:Carcinogens; D019388:Cytochrome P-450 CYP1A2; D005982:Glutathione Transferase; D007527:Isoenzymes; C504573:CYP1A2 protein, human; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1