title: A higher degree of LINE-1 methylation in peripheral blood mononuclear cells, a one-carbon nutrient related epigenetic alteration, is associated with a lower risk of developing cervical intraepithelial neoplasia.
abstract: OBJECTIVE
  The objective of the study was to evaluate LINE-1 methylation as an intermediate biomarker for the effect of folate and vitamin B12 on the occurrence of higher grades of cervical intraepithelial neoplasia (CIN ≥ 2).
  
  
  METHODS
  This study included 376 women who tested positive for high-risk human papillomaviruses and were diagnosed with CIN ≥ 2 (cases) or CIN ≤ 1 (non-cases). CIN ≥ 2 (yes/no) was the dependent variable in logistic regression models that specified the degree of LINE-1 methylation of peripheral blood mononuclear cells (PBMCs) and of exfoliated cervical cells (CCs) as the independent predictors of primary interest. In analyses restricted to non-cases, PBMC LINE-1 methylation (≥ 70% versus <70%) and CC LINE-1 methylation (≥ 54% versus <54%) were the dependent variables in logistic regression models that specified the circulating concentrations of folate and vitamin B12 as the primary independent predictors.
  
  
  RESULTS
  Women in the highest tertile of PBMC LINE-1 methylation had 56% lower odds of being diagnosed with CIN ≥ 2 (odds ratio 0.44, 95% confidence interval 0.24-0.83, P = 0.011), whereas there was no significant association between degree of CC LINE-1 methylation and CIN ≥ 2 (odds ratio 0.86, 95% confidence interval 0.51-1.46, P = 0.578). Among non-cases, women with supraphysiologic concentrations of folate (>19.8 ng/mL) and sufficient concentrations of plasma vitamin B12 (≥ 200.6 ng/mL) were significantly more likely to have highly methylated PBMCs compared with women with lower folate and lower vitamin B12 (odds ratio 3.92, 95% confidence interval 1.06-14.52, P = 0.041). None of the variables including folate and vitamin B12 were significantly associated with CC LINE-1 methylation.
  
  
  CONCLUSIONS
  These results suggest that a higher degree of LINE-1 methylation in PBMCs, a one-carbon nutrient-related epigenetic alteration, is associated with a lower risk of developing CIN.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA. piyathic@uab.edu
authors.forename: Chandrika J
authors.initials: CJ
authors.lastname: Piyathilake
authors.forename: Maurizio
authors.initials: M
authors.lastname: Macaluso
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Suguna
authors.initials: S
authors.lastname: Badiga
authors.forename: Nuzhat R
authors.initials: NR
authors.lastname: Siddiqui
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Edward E
authors.initials: EE
authors.lastname: Partridge
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johanning
mesh_terms: D000328:Adult; D015415:Biomarkers; D002244:Carbon; D016022:Case-Control Studies; D002584:Cervix Uteri / Q000166:cytology; D016001:Confidence Intervals; D019175:DNA Methylation; D003850:Deoxyribonuclease I / Q000378:metabolism*; D057890:Epigenomics; D005260:Female; D005492:Folic Acid / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D016015:Logistic Models; D008745:Methylation; D008875:Middle Aged; D016017:Odds Ratio; D030361:Papillomavirus Infections; D017697:Premenopause; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014805:Vitamin B 12 / Q000097:blood; D014803:Vitamin B Complex / Q000097:blood; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000821:virology
chemical_list: D015415:Biomarkers; D014803:Vitamin B Complex; D002244:Carbon; D005492:Folic Acid; D003850:Deoxyribonuclease I; C538849:LINE-1 endonuclease, human; D014805:Vitamin B 12