title: A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era.
abstract: BACKGROUND
  Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk.
  
  
  METHODS
  The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN.
  
  
  RESULTS
  The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017).
  
  
  CONCLUSIONS
  This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.
authors.affiliation: The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Suguna
authors.initials: S
authors.lastname: Badiga
authors.affiliation: Biosciences Division, Center for Cancer and Metabolism, SRI International, Menlo Park, California, United States of America.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johanning
authors.affiliation: The Department of Pediatrics, Division of Biostatistics and Epidemiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Macaluso
authors.affiliation: The Department of Community Health Outcomes and System, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Andres
authors.initials: A
authors.lastname: Azuero
authors.affiliation: The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Chambers
authors.affiliation: The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Nuzhat R
authors.initials: NR
authors.lastname: Siddiqui
authors.affiliation: The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Chandrika J
authors.initials: CJ
authors.lastname: Piyathilake
mesh_terms: D000328:Adult; D000483:Alleles; D015415:Biomarkers; D016022:Case-Control Studies; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020084:Long Interspersed Nucleotide Elements; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)