The association between MTHFR 677C>T genotype and folate status and genomic and gene-specific DNA methylation in the colon of individuals without colorectal neoplasia

Abstract

Background: Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation.Objective: We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon.Design: We conducted a cross-sectional study of 336 men and women (age 19–92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O6-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively.Results: Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001).Conclusion: MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at clinicaltrials.gov as ISRCTN43577261.

The effect of diet on the intestinal epigenome

“…They observed no effect of folate status biomarkers on the CGI methylation of either gene but obtained some evidence of an inverse relationship between vitamin B12, which is also a factor in SAM metabolism, and methylation of ESR1. In a larger study of 336 men and women without colorectal neoplasia, Hanks et al found no effect of plasma folate, RBC folate or plasma homocysteine on global methylation, or on CGI methylation of ESR1, MYOD1, IGF2, N33, APC or MLH1, but they did observe a weak inverse relationship between serum folate and methylation of MGMT [58]. The possibility of a relationship between MTHFR 677C>T genotype and DNA methylation status was also examined in this study but no evidence of an effect was observed.…”

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer

“…Folate metabolisms is involved in various intracellular processes such as DNA methylation, cell proliferation and synthesis of nucleic and amino acids [179]. Genetic alterations in these genes may disrupt folate metabolism function, inducing DNA hypomethylation and consequently activating proto-oncogenes [180][181][182][183][184]. Thus, polymorphisms in folate metabolism genes may promote tumor development and modify sensitivity of tumor cells to platinum compounds.…”

“…MTHFR is a crucial enzyme in the folate metabolism. Several polymorphisms in this gene lead to a production of an enzyme with decreased activity and their effects have been linked with DNA hypomethylation, therefore influencing platinum therapy outcomes [180][181][182][183][184].…”

Features of folate cycle disorders in children with ASD

“…Polymorphisms of folate cycle enzymes are considered as a significant reason for thegenetic locationto the development of autistic disorders 6,7 . In addition, polymorphisms of genes involved in thefolic acid cycle are associated with hyperhomocysteinemia, cardiovascular catastrophes 8 and the later stage of dementia 9 , congenital anomalies, primarily the nervous system 5,10 , and pathology in pregnancy, including multiple spontaneous abortions 11 , a high risk of cancer developing, including colon and rectal 12 , due to a DNA methylation [13][14][15] . There are few reports of autism in adults and children suffered from Neuroinfectious diseases, mainly the opportunistic infections 10,16 .…”