title: Association of DNA methyltransferases 3A and 3B polymorphisms, and plasma folate levels with the risk of urothelial carcinoma.
abstract: BACKGROUND
  Interindividual genetic variations of human DNA methyltransferases (DNMTs), which involve the methyl donor from the folate-related one-carbon metabolism pathway, are hypothesized as a risk factor for urothelial carcinoma (UC). Therefore, we evaluated the role of gene-environment interaction in UC carcinogenesis.
  
  
  METHODS
  A hospital-based case-control study was conducted by recruiting 192 patients with UC and 381 controls. Their plasma folate levels were measured using a competitive immunoassay kit. In addition, DNMT3A -448A>G and DNMT3B -579G>T genotyping was evaluated using a polymerase chain reaction-restriction fragment length polymorphism technique. Multivariate logistic regression and 95% confidence intervals (CIs) were applied to estimate the UC risk.
  
  
  RESULTS
  We observed that patients with UC exhibited a higher prevalence rate of folate insufficiency (folate levels ≤6 ng/mL) compared with the controls (35.94% and 18.37%, respectively). Furthermore, folate levels were higher in the prevalent UC patients than in the incident UC patients. However, folate insufficiency was similarly associated with a nearly two-fold increase in the risk of UC regardless of the UC patient group. In addition, the frequencies of the variant alleles for DNMT3A and DNMT3B were 0.80 and 0.92, respectively, and no association was observed with UC risk. However, participants with a variant homozygous genotype of DNMT3B -579G>T and folate insufficiency or with high cumulative cigarette smoking exhibited an increased risk of UC.
  
  
  CONCLUSIONS
  Overall, environmental factors may contribute more significantly to UC carcinogenesis compared with genetic susceptibility. Future studies should investigate other polymorphisms of DNMT3A and DNMT3B to determine genetic susceptibility.
authors.affiliation: Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Chung
authors.affiliation: Department of Urology, China Medical University and Hospital, Taichung, Taiwan; Department of Medicine, College of Medicine, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Chao-Hsiang
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Medicine, College of Medicine, China Medical University and Hospital, Taichung, Taiwan; Department of Family Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chiu-Shong
authors.initials: CS
authors.lastname: Liu
authors.affiliation: Department of Urology, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Huang
authors.affiliation: Department of Urology, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Yi-Huei
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Ssu-Ning
authors.initials: SN
authors.lastname: Chien
authors.affiliation: Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Ping-Huan
authors.initials: PH
authors.lastname: Tsai
authors.affiliation: Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Hui-An
authors.initials: HA
authors.lastname: Hsieh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D005492:Folic Acid / Q000097:blood*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014571:Urologic Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D005492:Folic Acid; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human