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Table 5 Literature assessing associations between MTHFR 677 or 1298 variants and altered DNAm in healthy tissues

From: No evidence for association of MTHFR 677C>T and 1298A>C variants with placental DNA methylation

Study Type of DNAm assessed: specific assay Tissue Study size Results
Studies finding associations with DNAm
 Stern et al. (2000) [32] Genome-wide: radiolabeled methyl group incorporation assay Blood 677CC: N = 9 677TT: N = 10 677TT associated with approximately 40% higher [3H]-methyl acceptance capacity than 677CC (p = 0.04), reflecting global hypomethylation
 Castro et al. (2004) [34] Genome-wide: cytosine extension assay Blood 677CC/1298AA: N = 17 677CT/1298AA: N = 22 677TT/1298AA: N = 9 677CT/1298AC: N = 22 677CC/1298AC: N = 20 677CC/1298CC: N = 7 677TT associated with higher [3H]-dCTP relative incorporation compared to 677CC (p < 0.05). 677TT/1298AA and 677CC/1298CC associated with higher relative incorporation than 677CC/1298AA (p < 0.05)
 McKay et al. (2012) [31] Genome-wide: LUMA Candidate sites (N = 3): pyrosequencing Umbilical cord blood 677: N = 160 1298: N = 132 mother-infant pairs Maternal 677T allele associated with altered mean DNAm in IGF2 in infant cord blood (p = 0.017); maternal 1298C allele associated with altered DNAm at 1 CpG in ZNT5 (p = 0.012) in infant cord blood. No associations with genome-wide DNAm
 van Mil et al. (2014) [100] Candidate sites (N = 11): MassArray EpiTYPER Umbilical cord blood 677CC or 677CT: N = 413 677TT: N = 50 Maternal 677TT genotype associated with lower DNAm in infant blood at candidate CpG sites in NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR genes (p = 0.03)
 Weiner et al. (2014) [36] Genome-wide: Methyl Flash Methylated DNA Quantification Kit Blood 677CC: N = 40 677TT: N = 40 677TT associated with significantly lower mean DNA methylation compared to 677CC (p = 0.0034)
 Llanos et al. (2015) [37] LINE-1: pyrosequencing Female breast tissue 1298AA: N = 73 1298AC or 1298CC: N = 45 1298C allele associated with lower LINE-1 methylation (OR 0.96; 95% CI 0.93–0.98)
 Song et al. (2016) [101] Genome-wide: Illumina 450k array Female breast tissue Study population: N = 81 677T and 1298C alleles associated with differential methylation at 5 and 3 CpGs, respectively (unadjusted p value < 5.0 × 10−5). No sites reached significance at an adjusted p value < 0.05
Studies finding no association with DNAm
 Narayanan et al. (2004) [38] Genome-wide: radiolabeled methyl group incorporation assay Blood 677CC: N = 90 677CT: N = 84 677TT: N = 25 1298AA: N = 93 1298AC: N = 77 1298CC: N = 29 No altered DNAm in association with 677T or 1298C alleles
 Jung et al. (2011) [102] Genome-wide: LC/MS Blood (Folic acid supplemented/placebo) 677CC: N = 36/40 677CT: N = 36/34 677TT: N = 33/37 No altered DNAm between the 3-year folic acid-supplemented (0.8 mg/day) group and placebo group and no difference in DNAm when stratified by the MTHFR 677 genotype
 Gomes et al. (2012) [39] Genome-wide: IMDQ kit Blood 677CC: N = 72 677CT: N = 39 677TT: N = 12 No altered DNAm between MTHFR 677 genotype groups
 Ono et al. (2012) [103] Genome-wide: LUMA Blood 677CC: N = 112 677CT or 677TT: N = 272 1298AA: N = 254 1298AC or 1298CC: N = 130 No altered DNAm in association with MTHFR 677 or 1298 variants No interaction between genome-wide DNAm, folate intake, and MTHFR 677 or 1298 variants
 Hanks et al. (2013) [104] Genome-wide: LC/MS Candidate sites (N = 7): pyrosequencing Colon 677CC: N = 185 677CT: N = 119 677TT: N = 32 No difference in DNAm between MTHFR 677 genotype groups, even when accounting for folate biomarkers No significant difference in DNAm at ESR1, MYOD1, IGF2, N33, MLH1, MGMT, and APC genes by the genotype group
 de Arruda et al. (2013) [40] Genome-wide: IMDQ kit Oral epithelial cells 677CC: N = 17 677CT: N = 19 677TT: N = 8 No difference in DNAm between MTHFR 677 genotype groups
 Deroo et al. (2014) [105] LINE-1: pyrosequencing Blood Study population: N = 646 women without breast cancer N = 294 with breast cancer 677 or 1298 genotypes not associated with altered LINE-1 DNAm in women without breast cancer
 Louie et al. (2016) [106] Candidate sites (N = 3): bisulfite sequencing Sperm 677CC: N = 21 677CT: N = 19 677TT: N = 4 677 genotype not associated with altered DNAm at MEST, H19, or IG-GTL2 imprinted differentially methylated regions
 Wang et al. (2016) [41] Meta-analysis 11 studies 677: N = 1147 1298: N = 1053 No altered DNAm associated with 677T and 1298C alleles
Studies finding association with DNAm only with interaction with altered OCM nutrient status
 Friso et al. (2002) [33] Genome-wide: LC/MS Blood 677CC: N = 187 677TT: N = 105 677TT associated with approximately half the mean level of mCytosine than in the 677CC group (p < 0.0001). This effect was driven by TT individuals with low-folate status
 Shellnut et al. (2004) [107] Genome-wide: radiolabeled methyl group incorporation assay and LC/MS Blood 677CC: N = 22 677TT: N = 19 No significant difference in DNAm between 677TT and 677CC groups. In response to 7-week folaterepletion following 7-week folate depletion, significantly increased mean % change and raw change in DNAm in 677TT individuals (p = 0.04 and 0.03, respectively)
 Friso et al. (2005) [35] Genome-wide: LC/MS Blood 677CC/1298AA: N = 19 677TT/1298AA: N = 72 677CC/1298CC: N = 42 In the presence of low folate, 1298AA associated with lower genome-wide DNAm compared to 1298AC or 1298CC genotypes (p = 0.0001 and p = 0.021, respectively), and 677TT/1298AA associated with lower DNAm compared to 677CC/1298AA (p < 0.05) and 677CC/1298CC (p < 0.0001). In 677TT/1298AA individuals, DNAm significantly reduced in low-folate vs high-folate individuals (p < 0.0001)
 Axume et al. (2007) [108] Genome-wide: cytosine extension assay Blood 677CC: N = 14 677CT: N = 12 677TT: N = 17 677TT associated with lower DNAm compared to 677CC (p < 0.05) after 7-week folate restriction followed by 7-week folate repletion treatment
 La Merrill et al. (2012) [109] Genome-wide: LUMA Blood (pregnant women) 677CC: N = 31 677CT or 677TT: N = 164 1298AA: N = 158 1298AC or 1298CC: N = 37 677T or 1298C alleles not associated with altered genome-wide DNAm, but vitamin B6 deficiency and presence of 677T allele associated with hypomethylation (p = 0.02)
 Aarabi et al. (2015) [110] Genome-wide: RRBS Candidate sites (N = 6): pyrosequencing Sperm 677CC: N = 13 677CT or 677TT: N = 17 After 6 months of high-dose folic acid supplementation, there was significant reduction in methylation in intergenic regions in 677CC men, whereas 677CT or 677TT men had significantly reduced methylation in promoters, exons, introns, and intergenic regions (p < 0.05)
  1. LUMA luminometric methylation assay, LINE-1 LINE-1 repetitive elements, LC/MS liquid-chromatography tandem mass spectrometry, IMDQ imprint methylated DNA quantification
  2. Sample size given for each MTHFR SNP was assessed in publication. If the sample size of specific genotypes is not present, it was not reported in publication. The combined MTHFR 677/1298 genotypes are specified when available; otherwise, these SNPs were assessed independently from one another in the same sample population