title: Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN.
abstract: We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52, and 58) and enhancer site 7862 of human papillomavirus (HPV) 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of this study was to replicate our previous findings and, in addition, to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16-positive women diagnosed with either CIN 2+ or ≤CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and HPV 16m or those with higher plasma vitamin B12 and HPV 16m were 75% (P < 0.01) and 60% (P = 0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P = 0.03) and 40% (P = 0.07) increase in the odds of having a higher degree of HPV 16m, respectively. This study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama. piyathic@uab.edu.
authors.forename: Chandrika J
authors.initials: CJ
authors.lastname: Piyathilake
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Macaluso
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Chambers
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Suguna
authors.initials: S
authors.lastname: Badiga
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Nuzhat R
authors.initials: NR
authors.lastname: Siddiqui
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Bell
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Partridge
authors.affiliation: Department of Obstetrics & Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.affiliation: Department of Veterinary Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas and SRI International, Menlo Park, CA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johanning
mesh_terms: D000328:Adult; D001706:Biopsy; D018899:CpG Islands; D019175:DNA Methylation; D004279:DNA, Viral / Q000737:chemistry*; D004742:Enhancer Elements, Genetic; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005838:Genotype; D052162:Human papillomavirus 16; D006801:Humans; D008297:Male; D018977:Micronutrients / Q000097:blood; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000737:chemistry; D030361:Papillomavirus Infections / Q000097:blood / Q000821:virology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000737:chemistry; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014805:Vitamin B 12 / Q000097:blood*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000097:blood / Q000821:virology*
chemical_list: D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D018977:Micronutrients; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D005492:Folic Acid; D014805:Vitamin B 12