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Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    Effects of homocysteine lowering with B vitamins on cognitive aging; meta-analysis of 11 trials with cognitive data on 22,000 individuals
    Clarke, R. ; Bennett, D. ; Parish, S. ; Eussen, S.J.P.M. ; Groot, C.P.G.M. de - \ 2014
    American Journal of Clinical Nutrition 100 (2014)2. - ISSN 0002-9165 - p. 657 - 666.
    randomized controlled-trial - folic-acid supplementation - placebo-controlled trial - alzheimers-disease - older-adults - cardiovascular-disease - plasma homocysteine - stroke prevention - vascular-disease - double-blind
    Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
    Associations between medication use and homocysteine levels in an older population, and potential mediation by vitamin B12 and folate: data from the B-PROOF study
    Ham, A.C. ; Enneman, A.W. ; Dijk, S.C. van; Wijngaarden, J.P. van; Zwaluw, N.L. van der; Brouwer, E.M. ; Dhonukshe-Rutten, R.A.M. ; Groot, C.P.G.M. de; Witkamp, R.F. - \ 2014
    Drugs & Aging 31 (2014)8. - ISSN 1170-229X - p. 611 - 621.
    type-2 diabetes-mellitus - plasma homocysteine - folic-acid - cardiovascular risk - parkinsons-disease - essential-hypertension - serum concentrations - c677t polymorphism - pharmacy records - controlled-trial
    Background Elevated homocysteine levels are a risk indicator for cardiovascular disease, fractures and cognitive decline. Previous studies indicated associations between homocysteine levels and medication use, including antihypertensive, lipid-lowering and antidiabetic medication. However, results were often contradictory and inconclusive. Our objective was to study the associations established previously in more detail by sub-classifying medication groups, and investigate the potential mediating role of vitamin B12 and folate status. Materials and Methods Baseline data from the B-PROOF (B-vitamins for the PRevention Of Osteoporotic Fractures) study were used. We included 2,912 participants aged =65 years, with homocysteine levels of 12–50 µmol/L and creatinine levels =150 µmol/L, for whom self-reported medication data were available. We used multivariable linear regression models and analysis of covariance to assess the association between medication use and plasma homocysteine levels, and the potential mediation by serum vitamin B12 and folate. Results The mean age was 74 years (standard deviation, 6.5), 50 % were women, and median homocysteine levels were 14 µmol/L [interquartile range, 13–17 µmol/L]. Higher mean homocysteine levels were observed in users vs. non-users for diuretics (15.2 vs. 14.9, p = 0.043), high-ceiling sulphonamide diuretics (16.0 vs. 14.9, p <0.001), medication acting via the renin-angiotensin system (15.2 vs. 14.9, p = 0.029) and metformin (15.6 vs. 15.1, p = 0.006). Non-selective ß-blocker use was associated with lower mean homocysteine levels (14.4 vs. 15.0, p = 0.019). Only this association was mediated by an underlying association with vitamin B12 and folate levels. Conclusion The associations between homocysteine levels and medication use appear to be fairly modest. Our results suggest that medication use is unlikely to contribute to clinically relevant changes in plasma homocysteine levels.
    Reliability of Selected Antioxidants and Compounds Involved in One-Carbon Metabolism in Two Dutch Cohorts
    Leenders, M. ; Ros, M.M. ; Sluijs, I. van der; Boshuizen, H.C. ; Gils, C.H. van; Jansen, E.H.J.M. ; Bueno-de-Mesquita, H.B. - \ 2013
    Nutrition and Cancer 65 (2013)1. - ISSN 0163-5581 - p. 17 - 24.
    c-reactive protein - nutritional biomarkers - plasma homocysteine - oxidative stress - carotenoids - cancer - serum - tocopherol - retinol - design
    Many epidemiological studies assess nutritional status based on single blood measurements, without verifying if these remain reliable over repeated measurements. This study assessed the reliability over a period of 2 to 5yr of plasma carotenoids, vitamin C, retinol, tocopherols, and serum compounds involved in 1-carbon metabolism in a subsample of Dutch participants of European Prospective Investigation into Cancer and Nutrition (EPIC). Blood samples from 38 men from MORGEN-EPIC and 35 women from Prospect-EPIC were collected between 1993 and 1997 and again after 2 to 5yr. The reliability of plasma carotenoids, retinol, vitamin C, and tocopherols, and of serum folate, homocysteine, and vitamins B6 and B12 was estimated using an intraclass correlation coefficient (ICC). Serum homocysteine and vitamin B12 were highly reliable biomarkers, with ICCs of 0.91 and 0.75, respectively. All other analyzed biomarkers had a slight or fair reliability over several years (ICCs ranged from 0.17 to 0.56). Most examined biomarkers showed reliability values that may lead to considerable attenuation of the risk estimate when used as exposure assessment in a risk model. If multiple measurements are not available, the risk estimates can be adjusted for the regression dilution using the ICC as adjustment coefficient.
    Gene–environment and gene–gene interactions of specific MTHFR, MTR and CBS gene variants in relation to homocysteine in black South Africans
    Nienaber-Rousseau, C. ; Ellis, S.M. ; Moss, S. ; Boonstra, A. ; Towers, G.W. - \ 2013
    Gene 530 (2013)1. - ISSN 0378-1119 - p. 113 - 118.
    beta-synthase gene - coronary-artery-disease - plasma homocysteine - methylenetetrahydrofolate reductase - methionine synthase - risk-factors - cardiovascular-disease - heart-disease - vascular-disease - high prevalence
    The methylenetetrahydrofolate reductase (MTHFR), cystathione-beta-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 mu mol/L; p <0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 mu mol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p = 0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p = 0.003 and = 0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 IF genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations. Therefore, some of the investigated genotypes affected Hcy; residential area changed the way in which the CBS T833C/844ins68 SNPs influenced Hcy concentrations highlighting the importance of environmental factors; and gene-gene interactions allude to epistalic effects. (C) 2013 Elsevier B.V. All rights reserved.
    Systematic review with dose-response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned’s prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons
    Dullemeijer, C. ; Souverein, O.W. ; Doets, E.L. ; Voet, H. van der; Wijngaarden, J.P. van; Boer, W.J. de; Plada, M. ; Dhonukshe-Rutten, R.A.M. ; Veld, P.H. in 't; Cavelaars, A.J.E.M. ; Groot, C.P.G.M. de; Veer, P. van 't - \ 2013
    American Journal of Clinical Nutrition 97 (2013)2. - ISSN 0002-9165 - p. 390 - 402.
    b-vitamins - folic-acid - homocysteine concentration - nutritional-status - multivitamin supplementation - methylmalonic acid - oral vitamin-b-12 - older-adults - plasma homocysteine - cognitive function
    Background: Many randomized controlled trials (RCTs) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers. The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence. Objective: We systematically reviewed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12 status and estimated dose-response relations with the use of a meta-analysis. Design: This systematic review included all RCTs, prospective cohort studies, nested case-control studies, and cross-sectional studies in healthy adult populations published through January 2010 that supplied or measured dietary vitamin B-12 intake and measured vitamin B-12 status as serum or plasma vitamin B-12, methylmalonic acid (MMA), or holotranscobalamin. We calculated an intake-status regression coefficient () for each individual study and calculated the overall pooled and SE () by using random-effects meta-analysis on a double-log scale. Results: The meta-analysis of observational studies showed a weaker slope of dose-response relations than the meta-analysis of RCTs. The pooled dose-response relation of all studies between vitamin B-12 intake and status indicated that a doubling of the vitamin B-12 intake increased vitamin B-12 concentrations by 11% (95% CI: 9.4%, 12.5%). This increase was larger for studies in elderly persons (13%) than in studies in adults (8%). The dose-response relation between vitamin B-12 intake and MMA concentrations indicated a decrease in MMA of 7% (95% CI: -10%, -4%) for every doubling of the vitamin B-12 intake. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to seriously alter these results. Conclusion: The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of populations.
    Homocysteine, progression of ventricular enlargement, and cognitive decline. The Second Manifestations of ARTerial disease-Magnetic Resonance Study
    Jochemsen, H.M. ; Kloppenborg, R.P. ; Groot, C.P.G.M. de; Kampman, E. ; Mali, W.P. ; Graaf, C. de; Geerlings, M.I. - \ 2013
    Alzheimer's & Dementia 9 (2013)3. - ISSN 1552-5260 - p. 302 - 309.
    brain atrophy - plasma homocysteine - risk-factor - folic-acid - probabilistic segmentation - elderly individuals - smart-mr - dementia - impairment - lesions
    Background Homocysteine may be a modifiable risk factor for cognitive decline and brain atrophy, particularly in older persons. We examined whether homocysteine increased the risk for cognitive decline and brain atrophy, and evaluated the modifying effect of age. Methods Within the Second Manifestations of ARTerial disease-Magnetic Resonance study—a prospective cohort study among patients with atherosclerotic disease—longitudinal analyses were performed in 663 patients (mean age: 57 ± 9 years; follow-up: 3.9 ± 0.4 years). At baseline and follow-up, brain segmentation on magnetic resonance imaging was used to quantify relative (%) cortical, ventricular, and global brain volumes, and z-scores of memory and executive functioning were calculated. Linear regression analysis was used to estimate associations of homocysteine (per standard deviation increase) and hyperhomocysteinemia (HHCY) with brain volumes, memory, and executive functioning at follow-up, adjusted for baseline brain volume, memory, and executive functioning, respectively, and age, sex, and vascular risk factors. Furthermore, interaction terms between homocysteine and age (continuous) were added. Results Significant interactions were observed between total plasma homocysteine (tHcy) and age with cortical, ventricular, and global brain volume (for all three measures: P <.05), and between HHCY and age with executive functioning (P = .04), and results were stratified by age. In patients aged =65 years, increasing tHcy level and HHCY were significantly associated with progression of ventricular enlargement (B = 0.07%, 95% confidence interval [CI]: 0.01% to 0.13% and B = 0.16%, 95% CI: 0.01% to 0.31%, respectively) and with a decline in executive function (B = -0.29, 95% CI: -0.54 to -0.04 and B = -0.84, 95% CI: -1.37 to -0.32, respectively). Conclusion Elevated tHcy was related to progression of ventricular enlargement and increased the risk for a decline in executive functioning in older persons
    No Effect of Folic Acid Supplementation on Global DNA Methylation in Men and Women with Moderately Elevated Homocysteine
    Jung, A.Y. ; Smulders, Y. ; Verhoef, P. ; Kok, F.J. ; Blom, H. ; Kok, R.M. ; Kampman, E. ; Durga, J. - \ 2011
    PLoS ONE 6 (2011)9. - ISSN 1932-6203
    methylenetetrahydrofolate reductase - folate supplementation - plasma homocysteine - colorectal-cancer - controlled-trial - common mutation - older-adults - human-colon - hypomethylation - gene
    A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = -20.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes.
    Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats
    LeBlanc, J.G. ; Sybesma, W.F.H. ; Starrenburg, M. ; Sesma, F. ; Vos, W.M. de; Giori, G.S. de; Hugenholtz, J. - \ 2010
    Nutrition 26 (2010)7. - ISSN 0899-9007 - p. 835 - 841.
    neural-tube defects - folic-acid - riboflavin status - plasma homocysteine - dietary-folate - bacteria - bioavailability - prevention - vitamin - propionibacteria
    Objective: The aim of this study was to establish the bioavailability of different folates produced by engineered Lactococcus lactis strains using a rodent depletion-repletion bioassay. Methods: Rats were fed a folate-deficient diet, which produces a reversible subclinical folate deficiency, supplemented with different L lactis cultures that were added as the only source of folate. Three bacterial strains that overexpressed the folC, folKE, or folC + KE genes were used. These strains produce folates with different poly glutamyl tail lengths. The growth response of the rats and the concentration of folates in different organs and blood samples were monitored. Results: The folate produced by the engineered strains was able to compensate the folate depletion in the diet and showed similar bioavailability compared with commercial folic acid that is normally used for food fortification. Folate concentrations in organ and blood samples increased significantly in animals that received the folate-producing strains compared with those that did not receive bacterial supplementation. Hematologic studies also showed that administration of the L towns strains was able to revert a partial megaloblastic anemia caused by folate deficiency. No significant differences were observed in the bioavailability of folates containing different glutamyl tail lengths. Conclusion: To our knowledge, this is the first study that demonstrated that folates produced by engineered lactic acid bacteria represent a bioavailable source of this essential vitamin. (C) 2010 Elsevier Inc. All rights reserved.
    Inhibition of methylation decreases osteoblast differentiation via a non-DNA-dependent methylation mechanism
    Vaes, B.L.T. ; Lute, C. ; Woning, S.P. van der; Piek, E. ; Vermeer, J. ; Blom, H.J. ; Mathers, J.C. ; Müller, M.R. ; Groot, C.P.G.M. de; Steegenga, W.T. - \ 2010
    Bone 46 (2010)2. - ISSN 8756-3282 - p. 514 - 523.
    bone-mineral density - arginine methylation - s-adenosylhomocysteine - postmenopausal women - plasma homocysteine - gene-expression - cpg methylation - hip fracture - adenosylmethionine - transcription
    S-adenosylmethionine (SAM)-dependent methylation of biological molecules including DNA and proteins is rapidly being uncovered as a critical mechanism for regulation of cellular processes. We investigated the effects of reduced SAM-dependent methylation on osteoblast differentiation by using periodate oxidized adenosine (ADOX), an inhibitor of SAM-dependent methyltransferases. The capacity of this agent to modulate osteoblast differentiation was analyzed under non-osteogenic control conditions and during growth factor-induced differentiation and compared with the effect of inhibition of DNA methylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR). Without applying specific osteogenic triggers, both ADOX and 5-Aza-CdR induced mRNA expression of the osteoblast markers Alp, Osx, and Ocn in murine C2C12 cells. Under osteogenic conditions, ADOX inhibited differentiation of both human mesenchymal stem cells and C2C12 cells. Gene expression analysis of early (Msx2, Dlx5, Runx2) and late (Alp, Osx, Ocn) osteoblast markers during bone morphogenetic protein 2-induced C2C12 osteoblast differentiation revealed that ADOX only reduced expression of the late phase Runx2 target genes. By using a Runx2-responsive luciferase reporter (6xOSE), we showed that ADOX reduced the activity of Runx2, while 5-Aza-CdR had no effect. Taken together, our data suggest that decreased SAM-dependent methyltransferase activity leads to impaired osteoblast differentiation via non-DNA-dependent methylation mechanisms and that methylation is a regulator of Runx2-controlled gene expression.
    Body Mass Index Is an Important Determinant of Methylation Biomarkers in Women of Reproductive Ages
    Driel, L.M.J.W. van; Eijkemans, M.J.C. ; Jonge, R. de; Vries, J.H.M. de; Meurs, J.B.J. van; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2009
    The Journal of Nutrition 139 (2009)12. - ISSN 0022-3166 - p. 2315 - 2321.
    intracellular s-adenosylhomocysteine - congenital heart-defects - plasma homocysteine - n-methyltransferase - vitamin-b-6 deficiency - dna hypomethylation - spectrometry method - adenosylmethionine - disease - risk
    B vitamin deficiencies lead to moderate hyperhomocysteinemia, which has been associated with health and disease. However, concomitant derangements in cellular methylation, reflected by altered plasma S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) concentrations, may be the primary cause. Therefore, we identified determinants of homocysteine, SAM, and SAH concentrations in 336 women, aged 20–48 y, as part of a large study focusing on risk factors for reproductive disorders. Blood was obtained to determine plasma SAM, SAH, and total homocysteine (tHcy), serum vitamin B-12 and folate, RBC folate concentrations, and the related single nucleotide polymorphisms 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C, methionine synthase reductase (MTRR) 66A > G, and nicotinamide N-methyltransferase IVS1–151G > A. Questionnaires provided information on demographics, lifestyles, and nutrient intakes. Correlation coefficients were calculated and multivariable associations were assessed with a general linear model. Serum folate was positively correlated with SAM concentrations (r = 0.159; P = 0.004). Folate and vitamin B-12 were not correlated with SAH concentrations or the SAM:SAH ratio but were inversely correlated with tHcy concentrations (serum folate r = –0.324; RBC folate r = –0.294; vitamin B-12 r = –0.307; P <0.01). From the multivariable analysis, BMI was the strongest determinant of SAM (standardized ß = 19.145; P <0.001) and SAH concentrations (standardized ß = 3.241; P = 0.010). MTHFR 677TT (standardized ß = 0.195; P = 0.001), B vitamin supplement use (standardized ß = –0.156; P <0.001) and dietary protein intake (standardized ß = –0.011; P <0.001) were the strongest determinants of tHcy concentrations. Thus, the determinants of SAM and SAH differ from those of tHcy concentrations. Given that BMI was a strong determinant of SAM concentrations, it should be included in future studies on cellular methylation.
    Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline
    Wilson, F.A. ; Borne, J.J.G.C. van den; Calder, A.G. ; O'Kennedy, N. ; Holtrop, G. ; Rees, W.D. ; Lobley, G.E. - \ 2009
    American Journal of Physiology. Endocrinology and Metabolism 296 (2009)4. - ISSN 0193-1849 - p. E702 - E713.
    amino-acids - plasma homocysteine - kinetics - methylation - insulin - disease - humans - deficiency - liver - methyltransferase
    Impaired transfer of methyl groups via the methionine cycle leads to plasma hyperhomocysteinemia. The tissue sources of plasma homocysteine in vivo have not been quantified nor whether hyperhomocysteinemia is due to increased entry or decreased removal. These issues were addressed in female rats offered diets with either adequate or excess methionine (additional methyl groups) with or without folate and choline (impaired methyl group transfer) for 5 wk. Whole body and tissue metabolism was measured based on isotopomer analysis following infusion with either [1-13C,methyl-2H3]methionine or [U-13C]methionine plus [1-13C]homocysteine. Although the fraction of intracellular methionine derived from methylation of homocysteine was highest in liver (0.18–0.21), most was retained. In contrast, the pancreas exported to plasma more of methionine synthesized de novo. The pancreas also exported homocysteine to plasma, and this matched the contribution from liver. Synthesis of methionine from homocysteine was reduced in most tissues with excess methionine supply and was also lowered in liver (P <0.01) with diets devoid of folate and choline. Plasma homocysteine concentration (P <0.001) and flux (P = 0.001) increased with folate plus choline deficiency, although the latter still represented
    Vitamin B12 Deficiency Stimulates Osteoclastogenesis via Increased Homocysteine and Methylmalonic Acid
    Vaes, B.L.T. ; Lute, C. ; Blom, H.J. ; Bravenboer, N. ; Vries, T.J. de; Everts, V. ; Dhonukshe-Rutten, R.A.M. ; Müller, M.R. ; Groot, C.P.G.M. de; Steegenga, W.T. - \ 2009
    Calcified Tissue International 84 (2009)5. - ISSN 0171-967X - p. 413 - 422.
    bone-mineral density - randomized controlled-trial - postmenopausal women - in-vitro - plasma homocysteine - pernicious-anemia - turnover markers - older persons - elderly-women - hip fracture
    The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B12 deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B12, Hcy, and MMA on differentiation and activity of bone cells. B12 deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B12 deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B12, Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase¿positive osteoclasts from mouse bone marrow. We observed that B12 did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B12 deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.
    Do dietary patterns in older men influence change in homocysteine through folate fortification? The Normative Aging Study
    Knoops, K.T.B. ; Spiro, A. ; Groot, C.P.G.M. de; Kromhout, D. ; Staveren, W.A. van; Tucker, K.L. - \ 2009
    Public Health Nutrition 12 (2009)10. - ISSN 1368-9800 - p. 1760 - 1766.
    folic-acid fortification - ischemic-heart-disease - acute coronary events - vitamin-b status - plasma homocysteine - serum folate - cardiovascular-disease - risk-factor - biochemical indicators - framingham nutrition
    Objective We aimed to describe the difference in B-vitamin intake and in plasma B-vitamin and homocysteine concentrations before and after folic acid fortification, in relation to dietary patterns. Design The Normative Aging Study (NAS) is a longitudinal study on ageing. Between 1961 and 1970, 2280 male volunteers aged 21¿80 years (mean 42 years) were recruited. Dietary intake data have been collected since 1987 and assessment of plasma B vitamins and homocysteine was added in 1993. Setting Boston, Massachusetts, USA. Subjects In the present study, 354 men who had completed at least one FFQ and one measurement of homocysteine, both before and after the fortification period, were included. Results Three dietary patterns were identified by cluster analysis: (i) a prudent pattern, with relatively high intakes of fruit, vegetables, low-fat milk and breakfast cereals; (ii) an unhealthy pattern, with high intakes of baked products, sweets and added fats; and (iii) a low fruit and vegetable but relatively high alcohol intake pattern. Dietary intake and plasma concentrations of folate increased significantly (P <0·05) among all dietary patterns after the fortification period. Homocysteine tended to decrease in supplement non-users and in subjects in the high alcohol, low fruit and vegetable dietary pattern (both P = 0·08). Conclusions After fortification with folic acid, folate intake and plasma folate concentration increased significantly in all dietary patterns. There was a trend towards greatest homocysteine lowering in the high alcohol, low fruit and vegetable group
    Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide
    Driel, L.M.J.W. van; Smedts, H.P.M. ; Helbing, W.A. ; Isaacs, A. ; Lindemans, J. ; Uitterlinden, A.G. ; Duijn, C.M. van; Vries, J.H.M. de; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2008
    European Heart Journal 29 (2008)11. - ISSN 0195-668X - p. 1424 - 1431.
    plasma homocysteine - gene - pregnancy - malformations - multivitamin - association - methylation - supplements - folate - bias
    Aims: Congenital heart defects (CHDs) have a multifactorial origin, in which subtle genetic factors and peri-conception exposures interact. We hypothesize that derangements in the homocysteine and detoxification pathways, due to a polymorphism in the nicotinamide N-methyltransferase (NNMT) gene, low maternal dietary nicotinamide intake, and medicine use in the peri-conception period, affect CHD risk. Methods and results: In 292 case and 316 control families, maternal peri-conception medicine use and low dietary intake of nicotinamide (13.8 mg/day) were independently associated with CHD risk [odds ratio (95% confidence interval) 1.6 (1.1¿2.3) and 1.5 (1.03¿2.3), respectively]. No significant association was found for the NNMT AG/AA genotype in mothers [0.9 (0.7¿1.3)], fathers [1.1 (0.8¿1.6)], or children [1.1 (0.8¿1.6)]. However, the combination of peri-conception medicine use, low dietary nicotinamide intake, and the NNMT AG/AA genotype in mothers or children showed risk of 2.7 (1.02¿8.1) and 8.8 (2.4¿32.5), respectively. Conclusion: Children carrying the NNMT A allele face additional CHD risk in combination with peri-conception exposure to medicines and/or a low dietary nicotinamide intake. These findings provide a first set of data against which future studies with larger sample sizes can be compared with.
    IANA task force on nutrition and cognitive decline with aging
    Gillette-Guyonnet, S. ; Abellan van Kan, G. ; Andrieu, S. ; Barberger-Gateau, P. ; Berr, C. ; Bonnefoy, M. ; Dartigues, J.F. ; Groot, C.P.G.M. de; Ferry, M. ; Galan, P. ; Hercberg, S. ; Jeandel, C. ; Morris, M.C. ; Nourhashemi, F. ; Payette, H. ; Poulain, J.P. ; Portet, F. ; Roussel, A.M. ; Ritz, P. ; Rolland, Y. ; Vellas, B. - \ 2007
    Journal of Nutrition, Health and Aging 11 (2007)2. - ISSN 1279-7707 - p. 132 - 152.
    incident alzheimer-disease - folic-acid fortification - life-style factors - dietary-fat intake - older persons - vitamin-e - oxidative stress - controlled-trial - plasma homocysteine - alpha-tocopherol
    Cognitive impairment can be influenced by a number of factors. The potential effect of nutrition has become a topic of increasing scientific and public interest. In particular, there are arguments that nutrients (food and/or supplements) such as vitamins, trace minerals, lipids, can affect the risk of cognitive decline and dementia, especially in frail elderly people at risk of deficiencies. Our objective in this paper is to review data relating diet to risk of cognitive decline and dementia, especially Alzheimer's disease (AD). We chose to focus our statements on homocysteine-related vitamins (B-vitamins), antioxidant nutrients (vitamins E and C, carotenoids, flavonoids, enzymatic cofactors) and dietary lipids. Results of epidemiological studies may sometimes appeared conflicting; however, certain associations are frequently found. High intake of saturated and trans-unsaturated (hydrogenated) fats were positively associated with increased risk of AD, whereas intake of polyunsaturated and monounsaturated fats were protective against cognitive decline in the elderly in prospective studies. Fish consumption has been associated with lower risk of AD in longitudinal cohort studies. Moreover, epidemiologic data suggest a protective role of the B-vitamins, especially vitamins B9 and B12, on cognitive decline and dementia. Finally, the results on antioxidant nutrients may suggest the importance of having a balanced combination of several antioxidant nutrients to exert a significant effect on the prevention of cognitive decline and dementia, while taking into account the potential adverse effects of these nutrients. There is no lack of attractive hypotheses to support research on the relationships between nutrition and cognitive decline. It is important to stress the need to develop further prospective studies of sufficiently long duration, including subjects whose diet is monitored at a sufficiently early stage or at least before disease or cognitive decline exist. Meta analyses should be developed, and on the basis of their results the most appropriate interventional studies can be planned. These studies must control for the greatest number of known confounding factors and take into account the impact of the standard social determinants of food habits, such as the regional cultures, social status, and educational level.
    The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida
    Linden, I.J. van der; Heijer, M. den; Afman, L.A. ; Gellekink, H. ; Vermeulen, S.H. ; Kluijtmans, L.A.J. ; Blom, H.J. - \ 2006
    Journal of Molecular Medicine 84 (2006)12. - ISSN 0946-2716 - p. 1047 - 1054.
    periconceptional vitamin supplementation - neural-tube defects - plasma homocysteine - methylmalonic acid - flavoprotein - prevention - cobalamin
    The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in homocysteine remethylation. In some studies, the 66A>G polymorphism in the MTRR gene was associated with increased neural tube defect (NTD) risk. Using a case-control design, we studied the association between the MTRR 66A>G polymorphism and spina bifida risk in 121 mothers, 109 spina bifida patients, 292 control women, and 234 pediatric controls. Possible interactions between the MTRR 66A>G variant and the MTR 2756A>G polymorphism, the MTHFR 677C>T variant, plasma vitamin B12, and plasma methylmalonic acid (MMA) levels were examined in the 121 mothers and 292 control women. Meta-analyses were conducted to set the results of the case-control study in the context of eligible literature on the relation between the MTRR 66A>G variant and NTD risk. Finally, a transmission disequilibrium test was performed for 82 complete mother–father–child triads to test for preferential transmission of the MTRR risk allele. In our case-control study, the MTRR 66A>G polymorphism had no influence on spina bifida risk in children [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4–1.1]. The MTRR 66GG genotype increased maternal spina bifida risk by 2.1-fold (OR 2.1, 95% CI 1.3–3.3). This risk became more pronounced in combination with the MTHFR 677TT genotype (OR 4.0, 95% CI 1.3–12.5). Moreover, we demonstrate a possible interaction between the MTRR 66GG genotype and high plasma MMA levels (OR 5.5, 95% CI 2.2–13.5). The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04–2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46–2.01). These data show that the MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low.
    No added value of the methionine loading test in assessment for venous thrombosis and cardiovascular disease risk
    Keijzer, M. ; Verhoef, P. ; Borm, G.F. ; Blom, H.J. ; Heijer, M. den - \ 2006
    Thrombosis and Haemostasis 95 (2006)2. - ISSN 0340-6245 - p. 380 - 385.
    plasma homocysteine - vascular-disease - b-vitamins - folic-acid - hyperhomocysteinemia - metaanalysis - recommendations - variability - mthfr - diet
    Homocysteine is a risk factor for cardiovascular disease and venous thrombosis. Clinical guidelines differ in their recommendation whether or not to measure homocysteine after methionine loading. In this study, we investigated the added value of the methionine loading test next to fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease, using Receiver Operating Characteristic (ROC) curves. The analysis was performed in 185 patients with recurrent venous thrombosis, 130 patients with cardiovascular disease and 601 controls. The discriminatory power of the fasting homocysteine measurement alone for identifying subjects at risk of venous thrombosis expressed as the area under the ROC curve (AUC) was 0.61 (95%CI 0.56-0.66). Using both a fasting homocysteine measurement and a methionine loading test together yielded a similar AUC of 0.65 (95% CI 0.60-0.69), indicating no added value of methionine loading next to fasting homocysteine measurement in identifying subjects at risk for thrombosis. Similar results where found for cardiovascular disease, with an AUC of 0.62 (95% CI 0.57-0.67) for the fasting homocysteine measurement alone and an AUC of 0.62 (95% CI 0.57-0.67) for the combination of both the fasting and the postload homocysteine measurement. The methionine loading test has no added value next to measuring fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease and for that reason should not be used in clinical practice.
    Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamim B-12 deficiency: a randomized, placebo-controlled trial
    Eussen, S.J. ; Groot, C.P.G.M. de; Joosten, L.W. ; Bloo, R. ; Clarke, R. ; Ueland, P.M. ; Schneede, J. ; Blom, H.J. ; Hoefnagels, W.H. ; Staveren, W.A. van - \ 2006
    American Journal of Clinical Nutrition 84 (2006)2. - ISSN 0002-9165 - p. 361 - 370.
    cobalamin deficiency - plasma homocysteine - methylmalonic acid - folate-deficiency - elderly people - impairment - supplementation - dementia - depression - serum
    Background: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. Objective: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged 70 y with mild vitamin B-12 deficiency. Design: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 µg vitamin B-12, 1000 µg vitamin B-12 + 400 µg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. Results: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. Conclusion: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function
    Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: A randomized trial
    Olthof, M.R. ; Bots, M.L. ; Katan, M.B. ; Verhoef, P. - \ 2006
    PloS Clinical trials 1 (2006)1. - ISSN 1555-5887
    coronary-artery-disease - vascular endothelial dysfunction - homocysteine-lowering therapy - placebo-controlled trial - ischemic-heart-disease - healthy-human subjects - saturated fatty-acids - plasma homocysteine - dependent vasodilation - cardiovascular events
    Objectives: We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status. Design: This was a randomized, placebo-controlled, double-blind, crossover study. Setting: The study took place at Wageningen University in Wageningen in the Netherlands. Participants: Participants were 39 apparently healthy men and women, aged 50 - 70 y. Interventions: Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days. Outcome Measures: On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before ( t = 0 h, fasting) and 6 h ( t = 6 h) after methionine loading. Results: The mean (+/- SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 +/- 62.1 mu mol/l. Mean fasting FMD was 3.1 +/- 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 +/- 9.3 mu mol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 +/- 2.8 mu mol/l ( p<0.001 relative to placebo) and by 12.1 +/- 8.2 mu mol/l ( p<0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95% CI, - 0.6; 1.9), +0.2 FMD% (- 1.0; 1.3), and +0.3 FMD% ( - 0.8; 1.4), respectively. Conclusions: Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.
    Homocysteine and cognitive function in institutionalised elderly : a cross-sectional analysis
    Manders, M. ; Vasse, E. ; Groot, C.P.G.M. de; Staveren, W.A. van; Bindels, J.G. ; Blom, H.J. ; Hoefnagels, W.H.L. - \ 2006
    European Journal of Nutrition 45 (2006)2. - ISSN 1436-6207 - p. 70 - 78.
    alzheimers-disease - plasma homocysteine - cardiovascular-disease - impairment - scale - vitamin-b-12 - performance - deficiency - people - folate
    Several cross¿sectional, case¿control and prospective studies revealed a relation between homocysteine and cognitive function or dementia. These studies included either patient populations or healthy, community¿ dwelling elderly people. Aim of the study In this study we tested the hypothesis that homocysteine was inversely associated with cognitive function in a population of institutionalised elderly (aged ¿ 60 y; n = 157). For testing this hypothesis baseline data of a recently conducted intervention study in institutionalised elderly (median age 83 years) were used. Cognitive function was evaluated by the cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS¿cog). The association between fasting plasma homocysteine level and cognitive function was investigated by multiple linear regression analysis. In the crude model homocysteine concentration was not significantly related to ADAS¿cog score (ß = 0.061; p = 0.45).Age was found to be related to ADAS¿cog score (ß = 0.161; p <0.05). Adjusting for age did however not result in a relation between homocysteine and cognitive function. In our study no association was found between homocysteine and cognitive function in a population of very old institutionalised subjects
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