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The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects.

Kok DE, Dhonukshe-Rutten RA, Lute C, Heil SG, Uitterlinden AG, van der Velde N, van Meurs JB, van Schoor NM, Hooiveld GJ, de Groot LC, Kampman E, Steegenga WT - Clin Epigenetics (2015)

Bottom Line: The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects.Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development.Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.

ABSTRACT

Background: Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 μg folic acid and 500 μg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip.

Results: After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate.

Conclusions: Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

No MeSH data available.


Related in: MedlinePlus

Flow diagram for the selection of participants and the analysis of samples. aSelf-reported change in use of dietary supplements containing folic acid or vitamin B12. bSerum levels of folate or vitamin B12 and plasma levels of homocysteine. Abbreviations: CRP C-reactive protein, MTHFR methylenetetrahydrofolate reductase, SNP single nucleotide polymorphism, SWAN subset-quantile within array normalization
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Fig1: Flow diagram for the selection of participants and the analysis of samples. aSelf-reported change in use of dietary supplements containing folic acid or vitamin B12. bSerum levels of folate or vitamin B12 and plasma levels of homocysteine. Abbreviations: CRP C-reactive protein, MTHFR methylenetetrahydrofolate reductase, SNP single nucleotide polymorphism, SWAN subset-quantile within array normalization

Mentions: As shown in Fig. 1, 44 participants were randomized to the intervention with folic acid and vitamin B12, while 43 participants were assigned to the placebo group. Baseline characteristics of the participants are presented in Table 1. Inherent to the selection procedure for our study, participants with the methylenetetrahydrofolate reductase (MTHFR) (C677T) CC and TT genotypes were equally distributed among the groups. Age, body mass index, and serum levels of folate, vitamin B12, and plasma homocysteine at baseline did not differ between the two groups. The 2-year intervention with folic acid and vitamin B12 resulted in increased serum levels of both B-vitamins (folate median change 34.0 nmol/L; vitamin B12 median change 319 pmol/L) as well as decreased levels of homocysteine (median change −5.3 μmol/L). The changes in these levels were statistically significantly different from the ones observed in the placebo group (median change for folate 5.4 nmol/L, vitamin B12 30.4 pmol/L, and homocysteine −1.5 μmol/L, for all parameters p < 0.0001). Individual changes in levels of serum folate, vitamin B12, and plasma homocysteine are presented in Fig. 2.Fig. 1


The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects.

Kok DE, Dhonukshe-Rutten RA, Lute C, Heil SG, Uitterlinden AG, van der Velde N, van Meurs JB, van Schoor NM, Hooiveld GJ, de Groot LC, Kampman E, Steegenga WT - Clin Epigenetics (2015)

Flow diagram for the selection of participants and the analysis of samples. aSelf-reported change in use of dietary supplements containing folic acid or vitamin B12. bSerum levels of folate or vitamin B12 and plasma levels of homocysteine. Abbreviations: CRP C-reactive protein, MTHFR methylenetetrahydrofolate reductase, SNP single nucleotide polymorphism, SWAN subset-quantile within array normalization
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644301&req=5

Fig1: Flow diagram for the selection of participants and the analysis of samples. aSelf-reported change in use of dietary supplements containing folic acid or vitamin B12. bSerum levels of folate or vitamin B12 and plasma levels of homocysteine. Abbreviations: CRP C-reactive protein, MTHFR methylenetetrahydrofolate reductase, SNP single nucleotide polymorphism, SWAN subset-quantile within array normalization
Mentions: As shown in Fig. 1, 44 participants were randomized to the intervention with folic acid and vitamin B12, while 43 participants were assigned to the placebo group. Baseline characteristics of the participants are presented in Table 1. Inherent to the selection procedure for our study, participants with the methylenetetrahydrofolate reductase (MTHFR) (C677T) CC and TT genotypes were equally distributed among the groups. Age, body mass index, and serum levels of folate, vitamin B12, and plasma homocysteine at baseline did not differ between the two groups. The 2-year intervention with folic acid and vitamin B12 resulted in increased serum levels of both B-vitamins (folate median change 34.0 nmol/L; vitamin B12 median change 319 pmol/L) as well as decreased levels of homocysteine (median change −5.3 μmol/L). The changes in these levels were statistically significantly different from the ones observed in the placebo group (median change for folate 5.4 nmol/L, vitamin B12 30.4 pmol/L, and homocysteine −1.5 μmol/L, for all parameters p < 0.0001). Individual changes in levels of serum folate, vitamin B12, and plasma homocysteine are presented in Fig. 2.Fig. 1

Bottom Line: The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects.Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development.Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.

ABSTRACT

Background: Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 μg folic acid and 500 μg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip.

Results: After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate.

Conclusions: Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

No MeSH data available.


Related in: MedlinePlus