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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

The differentially methylated region within DIRAS3. Individual (dots) and median (lines) DNA methylation values for the positions within the identified differentially methylated regions (DMRs) for DIRAS3 (chromosome 1) before (black) and after (red) the intervention with folic acid and vitamin B12 (n = 44) or placebo (n = 43). The DMRs were identified using the DMRcate package [81]. Coordinates for the human genome are based on h19/GRCh37
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Fig4: The differentially methylated region within DIRAS3. Individual (dots) and median (lines) DNA methylation values for the positions within the identified differentially methylated regions (DMRs) for DIRAS3 (chromosome 1) before (black) and after (red) the intervention with folic acid and vitamin B12 (n = 44) or placebo (n = 43). The DMRs were identified using the DMRcate package [81]. Coordinates for the human genome are based on h19/GRCh37

Mentions: Identification and characterization of differentially methylated regions (DMRs), consisting of multiple consecutive positions, showed that 6 regions differed for the participants receiving folic acid and vitamin B12 versus placebo (BH-adjusted p value <0.05) (Table 3). Again, for a DMR of 11 positions within DIRAS3 the most pronounced difference (maximal 5.2 %) in DNA methylation changes was found (Table 3 and Fig. 4). For this DMR, the mean percentage of DNA methylation increased after intervention with folic acid and vitamin B12 (1.5 %), but decreased in the placebo group (−0.9 %). A similar pattern was found for NODAL (nodal growth differentiation factor) on chromosome 10, for which 2 consecutive positions located within the 3′ untranslated region (3′UTR) were identified. After intervention with folic acid and vitamin B12, the mean methylation for these positions increased with 1.2 %, whereas in the placebo group a modest decrease of −0.4 % was found.Table 3


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)

The differentially methylated region within DIRAS3. Individual (dots) and median (lines) DNA methylation values for the positions within the identified differentially methylated regions (DMRs) for DIRAS3 (chromosome 1) before (black) and after (red) the intervention with folic acid and vitamin B12 (n = 44) or placebo (n = 43). The DMRs were identified using the DMRcate package [81]. Coordinates for the human genome are based on h19/GRCh37
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: The differentially methylated region within DIRAS3. Individual (dots) and median (lines) DNA methylation values for the positions within the identified differentially methylated regions (DMRs) for DIRAS3 (chromosome 1) before (black) and after (red) the intervention with folic acid and vitamin B12 (n = 44) or placebo (n = 43). The DMRs were identified using the DMRcate package [81]. Coordinates for the human genome are based on h19/GRCh37
Mentions: Identification and characterization of differentially methylated regions (DMRs), consisting of multiple consecutive positions, showed that 6 regions differed for the participants receiving folic acid and vitamin B12 versus placebo (BH-adjusted p value <0.05) (Table 3). Again, for a DMR of 11 positions within DIRAS3 the most pronounced difference (maximal 5.2 %) in DNA methylation changes was found (Table 3 and Fig. 4). For this DMR, the mean percentage of DNA methylation increased after intervention with folic acid and vitamin B12 (1.5 %), but decreased in the placebo group (−0.9 %). A similar pattern was found for NODAL (nodal growth differentiation factor) on chromosome 10, for which 2 consecutive positions located within the 3′ untranslated region (3′UTR) were identified. After intervention with folic acid and vitamin B12, the mean methylation for these positions increased with 1.2 %, whereas in the placebo group a modest decrease of −0.4 % was found.Table 3

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