| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Epidemiology Branch [J. A. T.], Laboratory of Molecular Carcinogenesis [J. A. T.], Biostatistics Branch [D. M. U.], and Laboratory of Computational Biology and Risk Analysis [E. S., T. C., D. A. B.], National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710 [D. P., C. R.]; and Department of Surgery, Division of Urology, University of North Carolina, Chapel Hill, North Carolina 27599 [J. L. M.]
Arylamines are known bladder carcinogens and are an important constituent of tobacco smoke. The handling of arylamines in the body is complex and includes metabolism by NAT1 and NAT2, enzymes that play a role in both activation and detoxification of arylamines and their congeners. Both NAT1 and NAT2 are polymorphic, with alleles that have been shown to correlate with higher or lower enzyme activity. To explore the combined role of these genes and exposure on bladder cancer risk, we examined the NAT1 and NAT2 genotype in a case-control study of bladder cancer in which detailed exposure histories were available on all 230 cases and 203 frequency-matched controls. Using PCR-RFLP genotyping, we determined NAT2 genotype for the five most common alleles, NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14 (frequently referred to as WT, M1, M2, M3, and M4, respectively). Similarly, the NAT1 genotype was determined for the four most common alleles NAT1*3, NAT1*4, and NAT1*11, and the putative high-activity allele, NAT1*10. No association between NAT2 genotype and bladder cancer risk was found whether genotype was considered alone or in combination with smoking, in either stratified or logistic regression analysis that adjusted for age, sex, and race. Stratified and logistic regression analysis both demonstrated an increased risk for individuals carrying the NAT1*10 allele among smokers. There was evidence of a gene-dosage effect, such that those who were homozygous for the NAT1*10 allele had the highest risks. There was also evidence of a statistically significant gene-environment interaction, such that bladder cancer risk depends on both NAT1 genotype and smoking exposure. Interestingly, although NAT2 genotype did not influence risk either alone or in combination with smoking exposure, there was evidence of a statistically significant gene-gene-environment three-way interaction. Bladder cancer risk from smoking exposure is particularly high in those who inherit NAT2 slow alleles in combination with one or two copies of the NAT1*10 allele. A biological mechanism for this finding is suggested.
1 To whom requests for reprints should be addressed, at Molecular and Genetic Epidemiology Section, NIEHS, Mail Drop A3-05, P. O. Box 12233, Research Triangle Park, NC 27709. E-mail: taylor@niehs.nih.gov.
Received 2/20/98. Accepted 6/17/98.
This article has been cited by other articles:
|
|
 |
|
  T. Lao, W. Gu, and Q. Huang A meta-analysis on XRCC1 R399Q and R194W polymorphisms, smoking and bladder cancer risk Mutagenesis, November 1, 2008; 23(6): 523 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Yuan, K. K. Chan, G. A. Coetzee, J.E. Castelao, M. A. Watson, D. A. Bell, R. Wang, and M. C. Yu Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer Carcinogenesis, July 1, 2008; 29(7): 1386 - 1393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Liu, P.-Y. Hsiao, C.-C. Lee, J.-A. Lee, and H.-Y. Chen NAT2*7 Allele Is a Potential Risk Factor for Adult Brain Tumors in Taiwanese Population Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 661 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sanderson, G. Salanti, and J. Higgins Joint Effects of the N-Acetyltransferase 1 and 2 (NAT1 and NAT2) Genes and Smoking on Bladder Carcinogenesis: A Literature-based Systematic HuGE Review and Evidence Synthesis Am. J. Epidemiol., October 1, 2007; 166(7): 741 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, L. Jiao, Y. Li, M. A. Doll, D. W. Hein, M. L. Bondy, D. B. Evans, R. A. Wolff, R. Lenzi, P. W. Pisters, et al. Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer Carcinogenesis, January 1, 2006; 27(1): 103 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Broberg, J. Bjork, K. Paulsson, M. Hoglund, and M. Albin Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer Carcinogenesis, July 1, 2005; 26(7): 1263 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Grigorenko The Inherent Complexities of Gene-Environment Interactions J. Gerontol. B. Psychol. Sci. Soc. Sci., March 1, 2005; 60(suppl_Special_Issue_1): 53 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Schroeder, K. Conway, Y. Li, K. Mistry, D. A. Bell, and J. A. Taylor p53 Mutations in Bladder Cancer: Evidence for Exogenous versus Endogenous Risk Factors Cancer Res., November 1, 2003; 63(21): 7530 - 7538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tsuneoka, T. P. Dalton, M. L. Miller, C. D. Clay, H. G. Shertzer, G. Talaska, M. Medvedovic, and D. W. Nebert 4-Aminobiphenyl-Induced Liver and Urinary Bladder DNA Adduct Formation in Cyp1a2(-/-) and Cyp1a2(+/+) Mice J Natl Cancer Inst, August 20, 2003; 95(16): 1227 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gago-Dominguez, D. A. Bell, M. A. Watson, J.-M. Yuan, J.E. Castelao, D. W. Hein, K. K. Chan, G. A. Coetzee, R. K. Ross, and M. C. Yu Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2 Carcinogenesis, March 1, 2003; 24(3): 483 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stern, L. R. Johnson, D. A. Bell, and J. A. Taylor XPD Codon 751 Polymorphism, Metabolism Genes, Smoking, and Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1004 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stern, D. M. Umbach, R. M. Lunn, and J. A. Taylor DNA Repair Gene XRCC3 Codon 241 Polymorphism, Its Interaction with Smoking and XRCC1 Polymorphisms, and Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 939 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.T. Simmons and C. J. Portier Toxicogenomics: the new frontier in risk analysis Carcinogenesis, June 1, 2002; 23(6): 903 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Garte Metabolic Susceptibility Genes As Cancer Risk Factors: Time for a Reassessment? Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1233 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vineis, D. Marinelli, H. Autrup, J. Brockmoller, I. Cascorbi, A. K. Daly, K. Golka, H. Okkels, A. Risch, N. Rothman, et al. Current Smoking, Occupation, N-Acetyltransferase-2 and Bladder Cancer: A Pooled Analysis of Genotype-based Studies Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1249 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fronhoffs, T. Bruning, E. Ortiz-Pallardo, P. Brode, B. Koch, V. Harth, A. Sachinidis, H. M. Bolt, C. Herberhold, H. Vetter, et al. Real-time PCR analysis of the N-acetyltransferase NAT1 allele *3, *4, *10, *11, *14 and *17 polymorphism in squamous cell cancer of head and neck Carcinogenesis, September 1, 2001; 22(9): 1405 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Cascorbi, I. Roots, and J. Brockmoller Association of NAT1 and NAT2 Polymorphisms to Urinary Bladder Cancer: Significantly Reduced Risk in Subjects with NAT1*10 Cancer Res., July 1, 2001; 61(13): 5051 - 5056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stern, D. M. Umbach, C. H. van Gils, R. M. Lunn, and J. A. Taylor DNA Repair Gene XRCC1 Polymorphisms, Smoking, and Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., February 1, 2001; 10(2): 125 - 131. [Abstract] [Full Text]
|
|
|
|
 |
|
 M-W Yu, C-I Pai, S-Y Yang, T-J Hsiao, H-C Chang, S-M Lin, Y-F Liaw, P-J Chen, and C-J Chen Role of N-acetyltransferase polymorphisms in hepatitis B related hepatocellular carcinoma: impact of smoking on risk Gut, November 1, 2000; 47(5): 703 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. King, C. H. Teitel, and F. F. Kadlubar In vitro bioactivation of N-hydroxy-2-amino-{alpha}-carboline Carcinogenesis, July 1, 2000; 21(7): 1347 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krajinovic, C. Richer, H. Sinnett, D. Labuda, and D. Sinnett Genetic Polymorphisms of N-Acetyltransferases 1 and 2 and Gene-Gene Interaction in the Susceptibility to Childhood Acute Lymphoblastic Leukemia Cancer Epidemiol. Biomarkers Prev., June 1, 2000; 9(6): 557 - 562. [Abstract] [Full Text]
|
|
|
|
|
|
N. M. Probst-Hensch, D. A. Bell, M. A. Watson, P. L. Skipper, S. R. Tannenbaum, K. K. Chan, R. K. Ross, and M. C. Yu N-Acetyltransferase 2 Phenotype but not NAT1*10 Genotype Affects Aminobiphenyl-Hemoglobin Adduct Levels Cancer Epidemiol. Biomarkers Prev., June 1, 2000; 9(6): 619 - 623. [Abstract] [Full Text]
|
|
|
|
|
|
P. M. Marcus, R. B. Hayes, P. Vineis, M. Garcia-Closas, N. E. Caporaso, H. Autrup, R. A. Branch, J. Brockmöller, T. Ishizaki, A. E. Karakaya, et al. Cigarette Smoking, N-Acetyltransferase 2 Acetylation Status, and Bladder Cancer Risk: A Case-Series Meta-analysis of a Gene-Environment Interaction Cancer Epidemiol. Biomarkers Prev., May 1, 2000; 9(5): 461 - 467. [Abstract] [Full Text]
|
|
|
|
|
|
D. W. Hein, M. A. Doll, A. J. Fretland, M. A. Leff, S. J. Webb, G. H. Xiao, U.-S. Devanaboyina, N. A. Nangju, and Y. Feng Molecular Genetics and Epidemiology of the NAT1 and NAT2 Acetylation Polymorphisms Cancer Epidemiol. Biomarkers Prev., January 1, 2000; 9(1): 29 - 42. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. S. Whittemore and L. M. Nelson Study Design in Genetic Epidemiology: Theoretical and Practical Considerations J Natl Cancer Inst Monographs, December 1, 1999; 1999(26): 61 - 69. [Abstract] [Full Text]
|
|
|
|
|
|
M. Gross, T. Kruisselbrink, K. Anderson, N. Lang, P. McGovern, R. Delongchamp, and F. Kadlubar Distribution and Concordance of N-Acetyltransferase Genotype and Phenotype in an American Population Cancer Epidemiol. Biomarkers Prev., August 1, 1999; 8(8): 683 - 692. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
