Abstract
BackgroundStudies 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.MethodsThe 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.ResultsThe 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).ConclusionsThis 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.
Highlights
Folate, a water soluble B vitamin naturally present in fruits and vegetables, acts as a critical methyl donor for several molecular pathways (DNA methylation, synthesis and repair) necessary for cellular replication and maintenance
There have been convincing reports on the interaction between folate intake or circulating concentrations of folate and methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism in relation to the risk of colorectal cancer or adenoma [27,28]. These results suggested that folate status may alter the effects of MTHFR C677T polymorphism, resulting in the polymorphism being protective in the presence of high folate status or being a risk in the presence of inadequate folate status
Women with comparing those heterozygous (CT) or TT genotype and plasma folate concentrations,11.25 ng/mL were 2.4 fold more likely to be diagnosed with CIN 2+ compared to women with CT or TT genotype and plasma folate concentrations $11.25 ng/mL (OR = 2.41, 95% confidence interval (CI) = 1.09–5.48, P = 0.030)
Summary
A water soluble B vitamin naturally present in fruits and vegetables, acts as a critical methyl donor for several molecular pathways (DNA methylation, synthesis and repair) necessary for cellular replication and maintenance. Even though the reviews of the safety and toxicity of folate that were published prior to initiation of FA fortification in the US concluded that FA is safe under most circumstances even at supra-physiologic amounts, concerns have been raised about possible adverse effects of current folate intakes on several diseases including cancer [5,6,7] Despite these concerns, the debate continues about whether even more FA should be added to the food supply in the US. Our studies demonstrated that the mechanisms by which higher folate may exert protective effects against CIN 2+ are likely to be via folate’s positive influence on immune response or DNA methylation These results suggest that folate may still be used as a chemopreventive agent for HPV related cancers or as an adjunct to enhance the efficacy of therapeutic HPV vaccines. 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
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