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The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction.

Publication ,  Journal Article
Taylor, JA; Umbach, DM; Stephens, E; Castranio, T; Paulson, D; Robertson, C; Mohler, JL; Bell, DA
Published in: Cancer Res
August 15, 1998

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.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

August 15, 1998

Volume

58

Issue

16

Start / End Page

3603 / 3610

Location

United States

Related Subject Headings

  • White People
  • Urinary Bladder Neoplasms
  • Smoking
  • Polymorphism, Genetic
  • Oncology & Carcinogenesis
  • Occupations
  • Neoplasm Proteins
  • Middle Aged
  • Male
  • Logistic Models
 

Citation

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Taylor, J. A., Umbach, D. M., Stephens, E., Castranio, T., Paulson, D., Robertson, C., … Bell, D. A. (1998). The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res, 58(16), 3603–3610.
Taylor, J. A., D. M. Umbach, E. Stephens, T. Castranio, D. Paulson, C. Robertson, J. L. Mohler, and D. A. Bell. “The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction.Cancer Res 58, no. 16 (August 15, 1998): 3603–10.
Taylor JA, Umbach DM, Stephens E, Castranio T, Paulson D, Robertson C, et al. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res. 1998 Aug 15;58(16):3603–10.
Taylor JA, Umbach DM, Stephens E, Castranio T, Paulson D, Robertson C, Mohler JL, Bell DA. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res. 1998 Aug 15;58(16):3603–3610.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

August 15, 1998

Volume

58

Issue

16

Start / End Page

3603 / 3610

Location

United States

Related Subject Headings

  • White People
  • Urinary Bladder Neoplasms
  • Smoking
  • Polymorphism, Genetic
  • Oncology & Carcinogenesis
  • Occupations
  • Neoplasm Proteins
  • Middle Aged
  • Male
  • Logistic Models