title: Protective association of MTHFR polymorphism on cervical intraepithelial neoplasia is modified by riboflavin status.
abstract: OBJECTIVE
  We previously reported that women polymorphic for the methylenetetrahydrofolate reductase (MTHFR) gene were less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3 (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.21-0.78, P = 0.007). In the present study, we tested whether this protective association is modified by circulating riboflavin status in the same study population.
  
  
  METHODS
  Riboflavin status was assessed by the erythrocyte glutathione reductase assay and expressed in terms of an erythrocyte glutathione reductase activity coefficient. The status of MTHFR polymorphism, riboflavin, and circulating concentrations of folate, vitamins B12, A, E, and C, and total carotene were ascertained in 170 White and 265 African-American women positive for the cervical presence of high-risk human papilloma virus. Presence/absence of CIN 2 or 3 was determined histologically, and associations with risk factors were examined using multiple logistic regression. Eighty women with CIN 2 or 3 lesions were compared with 355 women without cervical lesions. Based on the median erythrocyte glutathione reductase activity coefficient of 1.4, women were grouped into low (>1.4) and high (< or =1.4) riboflavin status.
  
  
  RESULTS
  Women with MTHFR polymorphism and low riboflavin status were significantly less likely to have CIN 2 or 3 than was the referent group of women without the polymorphism and high riboflavin status (OR 0.35, 95% CI 0.13-0.92, P = 0.034). MTHFR polymorphism was not associated with CIN 2 or 3 in women with high riboflavin status (OR 0.51, 95% CI 0.22-1.19, P = 0.119), nor were any of the associations influenced by folate levels.
  
  
  CONCLUSIONS
  A further inactivation of polymorphic MTHFR by low riboflavin status and a resulting shift in the folate metabolic pathway toward DNA synthesis may explain these observations. The practical implications of this complex gene-nutrient-disease interaction will require further investigation.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA. piyathic@uab.edu
authors.forename: Chandrika J
authors.initials: CJ
authors.lastname: Piyathilake
authors.forename: Maria
authors.initials: M
authors.lastname: Azrad
authors.forename: Maurizio
authors.initials: M
authors.lastname: Macaluso
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johanning
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Cornwell
authors.forename: Edward E
authors.initials: EE
authors.lastname: Partridge
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Heimburger
mesh_terms: D000328:Adult; D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D016001:Confidence Intervals; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005492:Folic Acid / Q000097:blood; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D016017:Odds Ratio; D030361:Papillomavirus Infections / Q000453:epidemiology* / Q000473:pathology; D011110:Polymorphism, Genetic; D012256:Riboflavin / Q000097:blood*; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology* / Q000473:pathology / Q000517:prevention & control; D014803:Vitamin B Complex / Q000097:blood*; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology* / Q000473:pathology / Q000517:prevention & control
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid; D005980:Glutathione Reductase; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase; D012256:Riboflavin