title: NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses.
abstract: BACKGROUND
  Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent.
  
  
  METHODS
  We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports.
  
  
  RESULTS
  In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86).
  
  
  CONCLUSIONS
  The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer.
  
  
  CONCLUSIONS
  Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD 20852-7234, USA. montse@nih.gov
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Debra
authors.initials: D
authors.lastname: Silverman
authors.forename: Mustafa
authors.initials: M
authors.lastname: Dosemeci
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Gemma
authors.initials: G
authors.lastname: Castaño-Vinyals
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Claudine
authors.initials: C
authors.lastname: Samanic
authors.forename: Montserrat
authors.initials: M
authors.lastname: Torà
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; C478900:NAT2 protein, human