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4. B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness

Author

van Dijk, S.C., Enneman, A.W., van Meurs, J., Swart, K.M.A., Ham, A.H., van Wijngaarden, J.P., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., van Schoor, N.M., Dhonukshe-Rutten, R.A.M., de Groot, L.C.P.G.M., Lips, P., Uitterlinden, A.G., Blom, H., Geleijnse, J.M., Feskens, E., de Jongh, R.T., Smulders, Y.M., van den Meiracker, A.H., Mattace-Raso, F.U.S., and van der Velde, N.

Published
2014
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7. Homocysteine and the methylenetetrahydrofolate reductase 677C → T polymorphism in relation to muscle mass and strength, physical performance and postural sway

Author

Swart, K.M.A., Enneman, A.W., van Wijngaarden, J.P., van Dijk, S.C., Brouwer-Brolsma, E.M., Ham, A.C., Dhonukshe-Rutten, R.A.M., van der Velde, N., Brug, J., van Meurs, J.B.J., de Groot, L.C.P.G.M., Uitterlinden, A.G., Lips, P., and van Schoor, N.M.

Subjects
Aged -- Physiological aspects -- Food and nutrition, Muscle strength -- Research, Homocysteine -- Physiological aspects, Food/cooking/nutrition, Health
Abstract

BACKGROUND/OBJECTIVES: Elevated plasma homocysteine has been linked to reduced mobility and muscle functioning in the elderly. The relation of methylenetetrahydrofolate reductase (MTHFR) 677C → T polymorphism with these associations has not yet been studied. This study aimed to investigate (1) the association of plasma homocysteine and the MTHFR 677C → T polymorphism with muscle mass, handgrip strength, physical performance and postural sway; (2) the interaction between plasma homocysteine and the MTHFR 677C → T polymorphism. SUBJECTS/METHODS: Baseline data from the B-PROOF study (n = 2919, mean age = 74.1 ± 6.5) were used. Muscle mass was measured using dual X-ray absorptiometry, handgrip strength with a handheld dynamometer, and physical performance with walking-, chair stand- and balance tests. Postural sway was assessed on a force platform. The data were analyzed using regression analyses with plasma homocysteine levels in quartiles. RESULTS: There was a significant inverse association between plasma homocysteine and handgrip strength (quartile 4: regression coefficient B = - 1.14, 95% confidence interval (CI) = -1.96; -0.32) and physical performance score (quartile 3: B = - 0.53, 95% CI = -0.95; -0.10 and quartile 4: -0.94; 95% CI = -1.40; -0.48) in women only, independent of serum vitamin B12 and folic acid. No association was observed between the MTHFR 677C [right arrow] T polymorphism and the outcomes. High plasma homocysteine in the 677CC and 677CT genotypes, but not in the 677TT genotype, was associated with lower physical performance. CONCLUSIONS: Elevated plasma homocysteine concentrations are associated with reduced physical performance and muscle strength in older women. There is an urgent need for randomized controlled trials to examine whether lowering homocysteine levels might delay physical decline. European Journal of Clinical Nutrition (2013) 67, 743-748; doi: 10.1038/ejcn.2013.97; published online 22 May 2013 Keywords: homocysteine; MTHFR 677C → T polymorphism; mobility limitation; muscle strength; aged, INTRODUCTION Muscle tissue is progressively lost with aging, contributing to a decline in muscle strength. Muscle weakness and loss of muscle strength are risk factors of reduced physical functioning, increased [...]

Published
2013
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8. Assessment of the genetic and clinical determinants of fracture risk : genome wide association and mendelian randomisation study

Author

Trajanoska, Katerina, Morris, John A., Oei, Ling, Zheng, Hou Feng, Evans, David M., Kiel, Douglas P., Ohlsson, Claes, Richards, J.B., Rivadeneira, Fernando, Forgett, V., Leong, A., Ahmad, O.S., Laurin, C., Mokry, L.E., Ross, S., Elks, C.E., Bowden, J., Warrington, N.M., Kleinman, A., Willems, S.M., Wright, D., Day, F.R., Murray, A., Ruth, K.S., Tsilidis, K.K., Ackert-Bicknell, C.L., Bassett, J.H.D., van der Eerden, B.C.J., Gautvik, K., Reppe, S., Williams, G.R., Medina-Gómez, C., Estrada, K., Amin, N., Enneman, A.W., Li, G., Liu, C.T., Liu, Y., Xiao, S.M., Lee, S.H., Koh, J.M., Tang, N.L.S., Cummings, S.R., Brown, M., de Groot, L., Jukema, J.W., Lips, P., van Meurs, J.B.J., Smith, A.V., Tian, S., GEFOS/GENOMOS consortium, 23andMe research team, Universidad de Cantabria, Wellcome Trust, Epidemiology, Internal Medicine, Trajanoska, Katerina [0000-0002-3792-4296], Ohlsson, Claes [0000-0002-9633-2805], Apollo - University of Cambridge Repository, GEFOS/GENOMOS Consortium, and 23andMe Research Team

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, Adolescent, Osteoporotic fractures, Genome-wide association study, Orthopaedics, Fractures -- Risk factors, Health risk assessment, Fractures, Bone, Young Adult, 03 medical and health sciences, Bone Density, Risk Factors, Internal medicine, Genetic predisposition, Life Science, Humans, Multicenter Studies as Topic, Medicine, Genetic Predisposition to Disease, Risk factor, Aged, Femoral neck, VLAG, Bone mineral, Global Nutrition, Wereldvoeding, business.industry, ta1184, Research, ta3142, General Medicine, Odds ratio, Mendelian Randomization Analysis, Middle Aged, Confidence interval, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Ortopedi, Osteoporosis, Medical genetics, Human medicine, Bone density, business, Genome-Wide Association Study
Abstract

OBJECTIVES: To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk., DESIGN: Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach., SETTING: 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data., PARTICIPANTS: A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor., RESULTS: Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10−68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture., CONCLUSIONS: This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk., This research and the Genetic Factors for Osteoporosis (GEFOS) consortium have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS)., peer-reviewed

Published
2018
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9. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, X. (Xia), O'Reilly, P.F. (Paul), Aschard, H. (Hugues), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (J. Brent), Dupuis, J. (Josée), Ingelsson, E. (Erik), Karasik, D. (David), Pilz, D.T. (Daniela), Berry, D. (Diane), Kestenbaum, B. (Bryan), Zheng, J. (Jusheng), Luan, J. (Jianan), Sofianopoulou, E. (Eleni), Streeten, E.A. (Elizabeth), Albanes, D. (Demetrius), Lutsey, P.L. (Pamela), Yao, L. (Lu), Tang, W. (Weihong), Econs, M.J. (Michael), Wallaschofski, H. (Henri), Völzke, H. (Henry), Zhou, A. (Ang), Power, C. (Christopher), McCarthy, M.I. (Mark I.), Michos, E.D. (Erin D.), Boerwinkle, E. (Eric), Weinstein, S.J. (Stephanie J.), Freedman, N.D. (Neal D.), Huang, W.-Y. (Wen-Yi), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Groot, L.C.P.G.M.D. (Lisette C.P.G.M. De), Enneman, A.W. (Anke), Cupples, L.A. (Adrienne), Booth, S.L. (Sarah L.), Vasan, R. (Ramachandran), Liu, C.-T. (Ching-Ti), Zhou, Y. (Yanhua), Ripatti, S. (Samuli), Ohlsson, C. (Claes), Vandenput, L. (Liesbeth), Lorentzon, M. (Mattias), Hagen, K. (Knut), Shea, M.K. (M. Kyla), Houston, D.K. (Denise K.), Kritchevsky, S.B. (Stephen B.), Liu, Y. (YongMei), Lohman, K.K. (Kurt K.), Ferrucci, L. (Luigi), Peacock, M. (Munro), Gieger, C. (Christian), Beekman, M. (Marian), Slagboom, P.E. (Eline), Deelen, J. (Joris), Heemst, D.V. (DIana Van), Kleber, M.E. (Marcus), März, W. (Winfried), Boer, I.H. (Ian) de, Wood, A.C. (Alexis C.), Rotter, J.I. (Jerome I.), Rich, S.S. (Stephen), Robinson-Cohen, C. (Cassianne), Heijer, M. (Martin) den, Jarvelin, M.-R. (Marjo-Riitta), Cavadino, A. (Alana), Joshi, P.K. (Peter), Wilson, J.F. (James F.), Hayward, C. (Caroline), Kao, W.H.L. (Wen), Michaëlsson, K. (Karl), Trompet, S. (Stella), Zillikens, M.C. (Carola), Uitterlinden, A.G. (Andre G.), Rivadeneira Ramirez, F. (Fernando), Broer, L. (Linda), Zgaga, L. (Lina), Campbell, H. (Harry), Theodoratou, E. (Evropi), Farrington, S.M. (Susan M.), Timofeeva, M.N. (Maria N.), Dunlop, M.G. (Malcolm), Valdes, A.M., Tikkanen, E. (Emmi), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Kähönen, M. (Mika), Raitakari, O.T. (Olli T.), Mikkilä, V. (Vera), Ikram, M.A. (Arfan), Sattar, N. (Naveed), Jukema, J.W. (J. Wouter), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Forouhi, N.G. (Nita), Gundersen, T.E. (Thomas E.), Khaw, K.-T. (Kay-Tee), Butterworth, A.S. (Adam S.), Danesh, J. (John), Spector, T.D. (Timothy), Wang, T.J. (Thomas J.), Hypponen, E. (Elina), Kraft, P. (Peter), Kiel, D.P. (Douglas P.), Jiang, X. (Xia), O'Reilly, P.F. (Paul), Aschard, H. (Hugues), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (J. Brent), Dupuis, J. (Josée), Ingelsson, E. (Erik), Karasik, D. (David), Pilz, D.T. (Daniela), Berry, D. (Diane), Kestenbaum, B. (Bryan), Zheng, J. (Jusheng), Luan, J. (Jianan), Sofianopoulou, E. (Eleni), Streeten, E.A. (Elizabeth), Albanes, D. (Demetrius), Lutsey, P.L. (Pamela), Yao, L. (Lu), Tang, W. (Weihong), Econs, M.J. (Michael), Wallaschofski, H. (Henri), Völzke, H. (Henry), Zhou, A. (Ang), Power, C. (Christopher), McCarthy, M.I. (Mark I.), Michos, E.D. (Erin D.), Boerwinkle, E. (Eric), Weinstein, S.J. (Stephanie J.), Freedman, N.D. (Neal D.), Huang, W.-Y. (Wen-Yi), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Groot, L.C.P.G.M.D. (Lisette C.P.G.M. De), Enneman, A.W. (Anke), Cupples, L.A. (Adrienne), Booth, S.L. (Sarah L.), Vasan, R. (Ramachandran), Liu, C.-T. (Ching-Ti), Zhou, Y. (Yanhua), Ripatti, S. (Samuli), Ohlsson, C. (Claes), Vandenput, L. (Liesbeth), Lorentzon, M. (Mattias), Hagen, K. (Knut), Shea, M.K. (M. Kyla), Houston, D.K. (Denise K.), Kritchevsky, S.B. (Stephen B.), Liu, Y. (YongMei), Lohman, K.K. (Kurt K.), Ferrucci, L. (Luigi), Peacock, M. (Munro), Gieger, C. (Christian), Beekman, M. (Marian), Slagboom, P.E. (Eline), Deelen, J. (Joris), Heemst, D.V. (DIana Van), Kleber, M.E. (Marcus), März, W. (Winfried), Boer, I.H. (Ian) de, Wood, A.C. (Alexis C.), Rotter, J.I. (Jerome I.), Rich, S.S. (Stephen), Robinson-Cohen, C. (Cassianne), Heijer, M. (Martin) den, Jarvelin, M.-R. (Marjo-Riitta), Cavadino, A. (Alana), Joshi, P.K. (Peter), Wilson, J.F. (James F.), Hayward, C. (Caroline), Kao, W.H.L. (Wen), Michaëlsson, K. (Karl), Trompet, S. (Stella), Zillikens, M.C. (Carola), Uitterlinden, A.G. (Andre G.), Rivadeneira Ramirez, F. (Fernando), Broer, L. (Linda), Zgaga, L. (Lina), Campbell, H. (Harry), Theodoratou, E. (Evropi), Farrington, S.M. (Susan M.), Timofeeva, M.N. (Maria N.), Dunlop, M.G. (Malcolm), Valdes, A.M., Tikkanen, E. (Emmi), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Kähönen, M. (Mika), Raitakari, O.T. (Olli T.), Mikkilä, V. (Vera), Ikram, M.A. (Arfan), Sattar, N. (Naveed), Jukema, J.W. (J. Wouter), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Forouhi, N.G. (Nita), Gundersen, T.E. (Thomas E.), Khaw, K.-T. (Kay-Tee), Butterworth, A.S. (Adam S.), Danesh, J. (John), Spector, T.D. (Timothy), Wang, T.J. (Thomas J.), Hypponen, E. (Elina), Kraft, P. (Peter), and Kiel, D.P. (Douglas P.)

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018
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10. Folate and vitamin B12-related biomarkers in relation to brain volumes

Author

Zwaluw, N.L. van der, Brouwer-Brolsma, E.M., Rest, O. van de, Wijngaarden, J.P. van, Veld, P.H. in 't, Kourie, D.I., Swart, K.M.A., Enneman, A.W., Dijk, S.C. van, Velde, N. van der, Kessels, R.P.C., Smeets, P.A.M., Kok, F.J., Dhonukshe-Rutten, R.A.M., Groot, C.P.G.M. de, Zwaluw, N.L. van der, Brouwer-Brolsma, E.M., Rest, O. van de, Wijngaarden, J.P. van, Veld, P.H. in 't, Kourie, D.I., Swart, K.M.A., Enneman, A.W., Dijk, S.C. van, Velde, N. van der, Kessels, R.P.C., Smeets, P.A.M., Kok, F.J., Dhonukshe-Rutten, R.A.M., and Groot, C.P.G.M. de

Abstract

Contains fulltext : 162573.pdf (publisher's version ) (Open Access), Aim: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B12 status and brain volumes. We furthermore compared brain volumes of participants who received daily folic acid and vitamin B12 supplementation with participants who did not. Methods: Participants of the B-PROOF study (n = 2919) were assigned to 400 mu-g folic acid and 500 mu-g vitamin B12, or a placebo. After two years of intervention, T1-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B12, holotranscobalamin, and methylmalonic acid concentrations were measured. Results: Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (beta = -0.91, 95% CI -1.85-0.03; p = 0.06) and between serum folate and TBV (beta = -0.20, 95% CI -0.38, -0.02; p = 0.03). No significant associations were observed for serum vitamin B12 and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL, p = 0.03). Conclusions: Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B12 supplementation will be beneficial above and beyond normal dietary intake for brain health.

Published
2017

11. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

Zillikens, M.C. (Carola), Stolk, L. (Lisette), Broer, L. (Linda), Amin, N. (Najaf), Campos Obanda, N. (Natalia), Enneman, A.W. (Anke), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kloth, J.S.L. (Jacqueline), Launer, L.J. (Lenore), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Zhou, Y. (Yanhua), Duijn, C.M. (Cornelia) van, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Kiel, D.P. (Douglas P.), Zillikens, M.C. (Carola), Stolk, L. (Lisette), Broer, L. (Linda), Amin, N. (Najaf), Campos Obanda, N. (Natalia), Enneman, A.W. (Anke), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kloth, J.S.L. (Jacqueline), Launer, L.J. (Lenore), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Zhou, Y. (Yanhua), Duijn, C.M. (Cornelia) van, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), and Kiel, D.P. (Douglas P.)

Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body and appendicular lean body mass measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantl

Published
2017
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12. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., Kiel, D.P., Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., and Kiel, D.P.

Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10(-8)) or suggestively genome wide (p < 2.3 × 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Published
2017

13. Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia

Author

Dijk, S.C., van, Enneman, A.W., Swart, K.M.A., Wijngaarden, J.P., van, Ham, A.C., Jonge, R., Blom, H.J., Feskens, E.J.M., Geleijnse, J.M., Schoor, N.M., van, Dhonukshe-Rutten, R.A.M., Jongh, R.T., de, Lips, P., Groot, C.P.G.M., de, Uitterlinden, A.G., Meiracker, A.H., van den, Mattace-Raso, F.U.S., Velde, N., van der, Smulders, Y., Dijk, S.C., van, Enneman, A.W., Swart, K.M.A., Wijngaarden, J.P., van, Ham, A.C., Jonge, R., Blom, H.J., Feskens, E.J.M., Geleijnse, J.M., Schoor, N.M., van, Dhonukshe-Rutten, R.A.M., Jongh, R.T., de, Lips, P., Groot, C.P.G.M., de, Uitterlinden, A.G., Meiracker, A.H., van den, Mattace-Raso, F.U.S., Velde, N., van der, and Smulders, Y.

Abstract

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 μg) and folic acid (400 μg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (–1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514

Published
2016

14. Low vitamin D status is associated with more depressive symptoms in Dutch older adults

Author

Brouwer-Brolsma, E.M. (Elske), Dhonukshe-Rutten, R.A.M. (Rosalie), Wijngaarden, J.P. (Janneke) van, Zwaluw, N.L. (N.) van der, Sohl, E. (Evelien), In’t Veld, P.H., Dijk, S.C. (Suzanne) van, Swart, K.M.A. (Karin), Enneman, A.W. (Anke), Ham, A.C. (Annelies), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Uitterlinden, A.G. (André), Lips, P. (Paul), Feskens, E.J.M. (Edith), Groot, L.C.P.G.M. (Lisette) de, Brouwer-Brolsma, E.M. (Elske), Dhonukshe-Rutten, R.A.M. (Rosalie), Wijngaarden, J.P. (Janneke) van, Zwaluw, N.L. (N.) van der, Sohl, E. (Evelien), In’t Veld, P.H., Dijk, S.C. (Suzanne) van, Swart, K.M.A. (Karin), Enneman, A.W. (Anke), Ham, A.C. (Annelies), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Uitterlinden, A.G. (André), Lips, P. (Paul), Feskens, E.J.M. (Edith), and Groot, L.C.P.G.M. (Lisette) de

Abstract

Purpose: The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged ≥65 years. Methods: 25-Hydroxyvitamin D (25(OH)D) was measured, and five ‘vitamin D-related genes’ were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. Results: A clear cross-sectional and pro

Published
2016
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15. Effects of two-year vitamin B12 and folic acid supplementation on depressive symptoms and quality of life in older adults with elevated homocysteine concentrations: Additional results from the B-Proof study, an RCT

Author

de Koning, E.J. (Elisa J.), Zwaluw, N.L. (N.) van der, Wijngaarden, J.P. (Janneke) van, Sohl, E. (Evelien), Brouwer-Brolsma, E.M. (Elske), Marwijk, H.W. (Harm) van, Enneman, A.W. (Anke), Swart, K.M.A. (Karin), Dijk, S.C. (Suzanne) van, Ham, A.C. (Annelies), Velde, N. (Nathalie) van der, Uitterlinden, A.G. (André), Penninx, B.W.J.H. (Brenda), Elders, P.J.M. (Petra), Lips, P. (Paul), Dhonukshe-Rutten, R.A.M. (Rosalie), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, de Koning, E.J. (Elisa J.), Zwaluw, N.L. (N.) van der, Wijngaarden, J.P. (Janneke) van, Sohl, E. (Evelien), Brouwer-Brolsma, E.M. (Elske), Marwijk, H.W. (Harm) van, Enneman, A.W. (Anke), Swart, K.M.A. (Karin), Dijk, S.C. (Suzanne) van, Ham, A.C. (Annelies), Velde, N. (Nathalie) van der, Uitterlinden, A.G. (André), Penninx, B.W.J.H. (Brenda), Elders, P.J.M. (Petra), Lips, P. (Paul), Dhonukshe-Rutten, R.A.M. (Rosalie), Schoor, N.M. (Natasja) van, and Groot, L.C.P.G.M. (Lisette) de

Abstract

Lowering elevated plasma homocysteine (Hcy) concentrations by supplementing vitamin B12 and folic acid may reduce depressive symptoms and improve health-related quality of life (HR-QoL) in older adults. This study aimed to test this hypothesis in a randomized controlled trial. Participants (N = 2919, ≥65 years, Hcy concentrations ≥12 µmol/L) received either 500 µg vitamin B12 and 400 µg folic acid daily or placebo for two years. Both tablets contained 15 µg vitamin D3. Depressive symptoms were measured with the Geriatric Depression Scale-15 (GDS-15). HR-QoL was assessed with the SF-12 Mental and Physical component summary scores and the EQ-5D Index score and Visual Analogue Scale. Differences in two-year change scores were analyzed with Analysis of Covariance (ANCOVA). Hcy concentrations decreased more in the intervention group, but two-year change scores of the GDS-15 and three of four HR-QoL measures did not differ between groups. The EQ-5D Index score declined less in the intervention group than in the placebo group (mean change 0.00 vs. −0.02, p = 0.004). In conclusion, two-year supplementation with vitamin B12 and folic acid in older adults with hyperhomocysteinemia showed that lowering Hcy concentrations does not reduce depressive symptoms, but it may have a small positive effect on HR-QoL.

Published
2016
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16. A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study

Author

Swart, K.M.A. (Karin), Ham, A.C. (Annelies), Wijngaarden, J.P. (Janneke) van, Enneman, A.W. (Anke), Dijk, S.C. (Suzanne) van, Sohl, E. (Evelien), Brouwer-Brolsma, E.M. (Elske), Zwaluw, N.L. (N.) van der, Zillikens, M.C. (Carola), Dhonukshe-Rutten, R.A.M. (Rosalie), Velde, N. (Nathalie) van der, Brug, J. (Hans), Uitterlinden, A.G. (André), Groot, L.C.P.G.M. (Lisette) de, Lips, P. (Paul), Schoor, N.M. (Natasja) van, Swart, K.M.A. (Karin), Ham, A.C. (Annelies), Wijngaarden, J.P. (Janneke) van, Enneman, A.W. (Anke), Dijk, S.C. (Suzanne) van, Sohl, E. (Evelien), Brouwer-Brolsma, E.M. (Elske), Zwaluw, N.L. (N.) van der, Zillikens, M.C. (Carola), Dhonukshe-Rutten, R.A.M. (Rosalie), Velde, N. (Nathalie) van der, Brug, J. (Hans), Uitterlinden, A.G. (André), Groot, L.C.P.G.M. (Lisette) de, Lips, P. (Paul), and Schoor, N.M. (Natasja) van

Abstract

Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12–50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU

Published
2016
Full Text
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17. Low vitamin D status is associated with more depressive symptoms in Dutch older adults

Author

Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., Sohl, E., in 't Veld, P.H., van Dijk, S.C., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Feskens, E.J.M., de Groot, C.P.G.M., Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., Sohl, E., in 't Veld, P.H., van Dijk, S.C., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Feskens, E.J.M., and de Groot, C.P.G.M.

Abstract

Purpose The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged =65 years. Methods 25-Hydroxyvitamin D (25(OH)D) was measured, and five ‘vitamin D-related genes’ were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. Results A clear cross-sectional and prospective association between serum 25(OH)D and depressive symptom score was observed. Fully adjusted models indicated a 22 % (RR 0.78, 95 % CI 0.68–0.89), 21 % (RR 0.79, 95 % CI 0.68–0.90), and 18 % (RR 0.82, 95 % CI 0.71–0.95) lower score of depressive symptoms in people in the second, third, and fourth 25(OH)D quartiles, when compared to people in the first quartile (P for trend

Published
2016

18. A randomized controlled trial to examine the effect of 2-year vitamin B12 and folic acid supplementation on physical performance, strength, and falling: additional findings from the B-PROOF study

Author

Swart, K.M.A., Ham, A.C., van Wijngaarden, J.P., Enneman, A.W., van Dijk, S.C., Sohl, E., Brouwer, E.M., van der Zwaluw, N.L., Zillikens, M.C., Dhonukshe-Rutten, R.A.M., van der Velde, N., Brug, J., Uitterlinden, A.G., de Groot, C.P.G.M., Lips, P., van Schoor, N.M., Swart, K.M.A., Ham, A.C., van Wijngaarden, J.P., Enneman, A.W., van Dijk, S.C., Sohl, E., Brouwer, E.M., van der Zwaluw, N.L., Zillikens, M.C., Dhonukshe-Rutten, R.A.M., van der Velde, N., Brug, J., Uitterlinden, A.G., de Groot, C.P.G.M., Lips, P., and van Schoor, N.M.

Abstract

Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12–50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0–12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95 % CI 0.9–1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95 % CI 1.1–1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies

Published
2016

19. Results of 2-year vitamin B treatment on cognitive performance

Author

van der Zwaluw, N.L., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., Brouwer, E.M., van de Rest, O., in 't Veld, P.H., Enneman, A.W., van Dijk, S.C., Ham, A.C., Swart, K.M.A., van der Velde, N., van Schoor, N.M., van der Cammen, T.J.M., Uitterlinden, A.G., Lips, P., Kessels, R.P.C., and de Groot, C.P.G.M.

Subjects
Global Nutrition, Wereldvoeding, impairment, Nutrition and Disease, homocysteine, elderly-patients, folate, folic-acid supplementation, placebo-controlled trial, Voeding en Ziekte, randomized controlled-trial, alzheimers-disease, double-blind, VLAG, metaanalysis
Abstract

Objective: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. Methods: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). Results: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) µmol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. Conclusions: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. Classification of evidence: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.

Published
2014

20. Cognitive performance: A cross-sectional study on serum vitamin D and its interplay with glucose homeostasis in Dutch older adults

Author

Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., Wijngaarden, J.P. van, Zwaluw, N.L. van der, Veld, P.H. in 't, Wins, S., Swart, K.M.A., Enneman, A.W., Ham, A.C., Dijk, S.C. van, Schoor, N.M. van, Velde, N. van der, Uitterlinden, A.G., Lips, P.J., Kessels, R.P.C., Steegenga, W.T., Feskens, E.J.M., Groot, C.P.G.M. de, Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., Wijngaarden, J.P. van, Zwaluw, N.L. van der, Veld, P.H. in 't, Wins, S., Swart, K.M.A., Enneman, A.W., Ham, A.C., Dijk, S.C. van, Schoor, N.M. van, Velde, N. van der, Uitterlinden, A.G., Lips, P.J., Kessels, R.P.C., Steegenga, W.T., Feskens, E.J.M., and Groot, C.P.G.M. de

Abstract

Item does not contain fulltext, OBJECTIVES: First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. MEASUREMENTS: Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. RESULTS: The overall median MMSE score was 29 (IQR 28-30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29-0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. CONCLUSION: Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance.

Published
2015

21. Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial

Author

Enneman, A.W. (Anke), Swart, K.M.A. (Karin), Wijngaarden, J.P. (Janneke) van, Dijk, S.C. (Suzanne) van, Ham, A.C. (Annelies), Brouwer-Brolsma, E.M. (Elske), Zwaluw, N.L. (N.) van der, Dhonukshe-Rutten, R.A.M. (Rosalie), Cammen, T.J.M. (Tischa) van der, Groot, L.C.P.G.M. (Lisette) de, Meurs, J.B.J. (Joyce) van, Lips, P. (Paul), Uitterlinden, A.G. (André), Zillikens, M.C. (Carola), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Enneman, A.W. (Anke), Swart, K.M.A. (Karin), Wijngaarden, J.P. (Janneke) van, Dijk, S.C. (Suzanne) van, Ham, A.C. (Annelies), Brouwer-Brolsma, E.M. (Elske), Zwaluw, N.L. (N.) van der, Dhonukshe-Rutten, R.A.M. (Rosalie), Cammen, T.J.M. (Tischa) van der, Groot, L.C.P.G.M. (Lisette) de, Meurs, J.B.J. (Joyce) van, Lips, P. (Paul), Uitterlinden, A.G. (André), Zillikens, M.C. (Carola), Schoor, N.M. (Natasja) van, and Velde, N. (Nathalie) van der

Abstract

High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.

Published
2015
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22. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Richards, J.B. (Brent), Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), and Richards, J.B. (Brent)

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation

Published
2015
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23. Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population

Author

van Dijk, S.C., Sohl, E., Oudshoorn, C., Enneman, A.W., Ham, A.C., Swart, K.M.A., van Wijngaarden, J.P., Brouwer, E.M., van der Zwaluw, N.L., Uitterlinden, A.G., de Groot, C.P.G.M., Dhonukshe-Rutten, R.A.M., Lips, P., van Schoor, N.M., Blom, H.J., Geleijnse, J.M., Feskens, E.J.M., van Dijk, S.C., Sohl, E., Oudshoorn, C., Enneman, A.W., Ham, A.C., Swart, K.M.A., van Wijngaarden, J.P., Brouwer, E.M., van der Zwaluw, N.L., Uitterlinden, A.G., de Groot, C.P.G.M., Dhonukshe-Rutten, R.A.M., Lips, P., van Schoor, N.M., Blom, H.J., Geleijnse, J.M., and Feskens, E.J.M.

Abstract

Background: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population. Design: cross-sectional. Setting/subjects: a subgroup of the B-PROOF study was included to determine associations between serum 25(OH)D and arterial stiffness and atherosclerosis (n = 567, 57% male, age 72.6 ± 5.6 years, mean serum 25(OH)D 54.6 ± 24.1 nmol/l). Methods: carotid intima media thickness (IMT) was assessed using ultrasonography and pulse wave velocity (PWV) was determined with applanation tonometry. Associations were tested using multivariable restricted cubic spline functions and stratified linear regression analysis. Results: the associations between serum 25(OH)D and carotid IMT or PWV were non-linear. Spline functions demonstrated a difference between 25(OH)D deficient and sufficient individuals. In serum 25(OH)D sufficient participants (=50 nmol/l; n = 287), a positive association with IMT and serum 25(OH)D was present (ß 1.24; 95%CI [0.002; 2.473]). PWV levels were slightly lower in vitamin D deficient individuals, but the association with 25(OH)D was not significant. Conclusion: our study demonstrates that associations of serum 25(OH)D and PWV and IMT in an elderly population are not linear. In particular from serum 25(OH)D levels of 50 nmol/l and up, there is a slight increase of IMT with increasing 25(OH)D levels.

Published
2015

24. Effect of vitamin B12 and folic acid supplementation on bone mineral density and quantitative ultrasound parameters in older people with an elevated plasma homocysteine level: B-PROOF, a randomized controlled trial

Author

Enneman, A.W., Swart, K.M.A., van Wijngaarden, J.P., van Dijk, S.C., Ham, A.C., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., Dhonukshe-Rutten, R.A.M., van der Cammen, T.J.M., de Groot, C.P.G.M., van Meurs, J.B.J., Lips, P., Uitterlinden, A.G., Zillikens, M.C., van Schoor, N.M., van der Velde, N., Enneman, A.W., Swart, K.M.A., van Wijngaarden, J.P., van Dijk, S.C., Ham, A.C., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., Dhonukshe-Rutten, R.A.M., van der Cammen, T.J.M., de Groot, C.P.G.M., van Meurs, J.B.J., Lips, P., Uitterlinden, A.G., Zillikens, M.C., van Schoor, N.M., and van der Velde, N.

Abstract

High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged =65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p <0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.

Published
2015

25. Results of 2-year vitamin B treatment on cognitive performance: Secondary data from an RCT

Author

Zwaluw, N.L. van der, Dhonukshe-Rutten, R.A.M., Wijngaarden, J.P. van, Brouwer-Brolsma, E.M., Rest, O. van de, Veld, P.H. in 't, Enneman, A.W., Dijk, S.C. van, Ham, A.C., Swart, K.M.A., Velde, N. van der, Schoor, N.M. van, Cammen, T.J.M. van der, Uitterlinden, A.G., Lips, P.J., Kessels, R.P.C., Groot, C.P.G.M. de, Zwaluw, N.L. van der, Dhonukshe-Rutten, R.A.M., Wijngaarden, J.P. van, Brouwer-Brolsma, E.M., Rest, O. van de, Veld, P.H. in 't, Enneman, A.W., Dijk, S.C. van, Ham, A.C., Swart, K.M.A., Velde, N. van der, Schoor, N.M. van, Cammen, T.J.M. van der, Uitterlinden, A.G., Lips, P.J., Kessels, R.P.C., and Groot, C.P.G.M. de

Abstract

Item does not contain fulltext, OBJECTIVE: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. METHODS: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 micromol/L. Participants received daily either a tablet with 400 microg folic acid and 500 microg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 microg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). RESULTS: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) micromol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) micromol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. CONCLUSIONS: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.

Published
2014

26. O1.16: Medication-related fall incidents in an older, ambulant population: the B-PROOF study

Author

Ham, A.C., primary, Swart, M.A., additional, Enneman, A.W., additional, van Dijk, S.C., additional, Oliai Araghi, S., additional, van Wijngaarden, J.P., additional, van der Zwaluw, N.L., additional, Brouwer-Brolsma, E.M., additional, Dhonukshe-Rutten, R.A.M., additional, van Schoor, N.M., additional, van der Cammen, T.J.M., additional, Lips, P., additional, de Groot, C.P.G.M., additional, Uitterlinden, A.G., additional, Witkamp, R.F., additional, Stricker, B.H.C., additional, and van der Velde, N., additional

Published
2014
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27. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B 12and folic acid on fracture incidence

Author

Wijngaarden, J.P. (Janneke) van, Dhonukshe-Rutten, R.A.M. (Rosalie), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Swart, K.M.A. (Karin), Enneman, A.W. (Anke), Dijk, S.C. (Suzanne) van, Brouwer-Brolsma, E.M. (Elske), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Brug, J. (Hans), Uitterlinden, A.G. (André), Lips, P. (Paul), Groot, L.C.P.G.M. (Lisette) de, Wijngaarden, J.P. (Janneke) van, Dhonukshe-Rutten, R.A.M. (Rosalie), Schoor, N.M. (Natasja) van, Velde, N. (Nathalie) van der, Swart, K.M.A. (Karin), Enneman, A.W. (Anke), Dijk, S.C. (Suzanne) van, Brouwer-Brolsma, E.M. (Elske), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Brug, J. (Hans), Uitterlinden, A.G. (André), Lips, P. (Paul), and Groot, L.C.P.G.M. (Lisette) de

Abstract

Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12and folate status are associated with an increased fracture risk. As vitamin B12and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design. The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration ( 12 mol/L). One group receives daily a tablet with 500 g vitamin B12and 400 g folic acid and the other group receives a placebo tablet. In both tablets 15 g (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i

Published
2011
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28. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Author

van Wijngaarden, J.P., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M.A., Enneman, A.W., van Dijk, S.C., Brouwer, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P., de Groot, C.P.G.M., van Wijngaarden, J.P., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M.A., Enneman, A.W., van Dijk, S.C., Brouwer, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P., and de Groot, C.P.G.M.

Abstract

Background Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (= 12 µmol/L). One group receives daily a tablet with 500 µg vitamin B12 and 400 µg folic acid and the other group receives a placebo tablet. In both tablets 15 µg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator. Discussion To our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semeste

Published
2011

29. The effect of B-vitamin supplementation on arterial stiffness in elderly. The B-PROOF trial

Author

Van Dijk, S.C., primary, Smulders, Y.M., additional, Enneman, A.W., additional, Swart, K.M.A., additional, Van Wijngaarden, J.P., additional, Ham, A.C., additional, Van der Zwaluw, N., additional, Brouwer-Brolsma, E., additional, Van Schoor, N.M., additional, Dhonokshe-Rutten, R.A.M., additional, de Groot, C.P.G.M., additional, Lips, P., additional, Uitterlinden, A.G., additional, de Jongh, R.T., additional, Blom, H.J., additional, Geleijnse, J.M., additional, Feskens, E.J., additional, Van den Meiracker, A.H., additional, Mattace-Raso, F.U.S., additional, and Van der Velde, N., additional

Published
2013
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