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1. Effectiveness of medication withdrawal in older fallers: Results from the improving medication prescribing to reduce risk of falls (IMPROveFALL) trial

Author

Boyé, N.D.A. (Nicole), Velde, N. (Nathalie) van der, De Vries, O.J. (Oscar J.), Lieshout, E.M.M. (Esther) van, Hartholt, K.A. (Klaas A.), Mattace-Raso, F.U.S. (Francesco U.S.), Lips, P. (Paul), Patka, P. (Peter), Van Beeck, E.F. (Ed F.), Cammen, T.J.M. (Tischa) van der, van der Cammen, T.J.M., Patka, P., Beeck, E.F. (Ed) van, van der Velde, N., Polinder, S. (Suzanne), Mattace Raso, F.U.S. (Francesco), Hartholt, K.A. (Klaas), Boyé, N.D.A., Looman, C.W.N. (Caspar), Lips, P., Vries, O.J. (Oscar) de, Kerver, A.J.H. (Albert J.H.), Boyé, N.D.A. (Nicole), Velde, N. (Nathalie) van der, De Vries, O.J. (Oscar J.), Lieshout, E.M.M. (Esther) van, Hartholt, K.A. (Klaas A.), Mattace-Raso, F.U.S. (Francesco U.S.), Lips, P. (Paul), Patka, P. (Peter), Van Beeck, E.F. (Ed F.), Cammen, T.J.M. (Tischa) van der, van der Cammen, T.J.M., Patka, P., Beeck, E.F. (Ed) van, van der Velde, N., Polinder, S. (Suzanne), Mattace Raso, F.U.S. (Francesco), Hartholt, K.A. (Klaas), Boyé, N.D.A., Looman, C.W.N. (Caspar), Lips, P., Vries, O.J. (Oscar) de, and Kerver, A.J.H. (Albert J.H.)

Abstract

Objectives: to investigate the effect of withdrawal of fall-risk-increasing-drugs (FRIDs) versus 'care as usual' on reducing falls in community-dwelling older fallers. Design: randomised multicentre trial. Participants: six hundred and twelve older adults who visited an Emergency Department (ED) because of a fall. Interventions: withdrawal of FRIDs. Main Outcomes and Measures: primary outcome was time to the first self-reported fall. Secondary outcomes were time to the second self-reported fall and to falls requiring a general practitioner (GP)-consultation or ED-visit. Intention-to-treat (primary) and a per-protocol (secondary) analysis were conducted. The hazard ratios (HRs) for time-to-fall were calculated using a Cox-regression model. Differences in cumulative incidence of falls were analysed using Poisson regression. Results: during 12 months follow-up, 91 (34%) control and 115 (37%) intervention participants experienced a fall; 35% of all attempted interventions were unsuccessful, either due to recurrence of the initial indication for prescribing, additional medication for newly diagnosed conditions or non-compliance. Compared to baseline, the overall percentage of users of =3 FRIDs at 12 months did not change in either the intervention or the control group. Our intervention did not have a significant effect on time to first fall (HR 1.17; 95% confidence interval 0.89-1.54), time to second fall (1.19; 0.78-1.82), time to first fall-related GP-consultation (0.66; 0.42-1.06) or time to first fall-related ED-visit (0.85; 0.43-1.68). Conclusion: in this population of complex multimorbid patients visiting an ED because of a fall, our single intervention of FRIDs-withdrawal was not effective in reducing falls.

Published
2017
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2. Effectiveness of medication withdrawal in older fallers: Results from the improving medication prescribing to reduce risk of falls (IMPROveFALL) trial

Author

Boyé, N.D.A. (Nicole), Velde, N. (Nathalie) van der, De Vries, O.J. (Oscar J.), Lieshout, E.M.M. (Esther) van, Hartholt, K.A. (Klaas A.), Mattace-Raso, F.U.S. (Francesco U.S.), Lips, P. (Paul), Patka, P. (Peter), Van Beeck, E.F. (Ed F.), Cammen, T.J.M. (Tischa) van der, van der Cammen, T.J.M., Patka, P., Beeck, E.F. (Ed) van, van der Velde, N., Polinder, S. (Suzanne), Mattace Raso, F.U.S. (Francesco), Hartholt, K.A. (Klaas), Boyé, N.D.A., Looman, C.W.N. (Caspar), Lips, P., Vries, O.J. (Oscar) de, Kerver, A.J.H. (Albert J.H.), Boyé, N.D.A. (Nicole), Velde, N. (Nathalie) van der, De Vries, O.J. (Oscar J.), Lieshout, E.M.M. (Esther) van, Hartholt, K.A. (Klaas A.), Mattace-Raso, F.U.S. (Francesco U.S.), Lips, P. (Paul), Patka, P. (Peter), Van Beeck, E.F. (Ed F.), Cammen, T.J.M. (Tischa) van der, van der Cammen, T.J.M., Patka, P., Beeck, E.F. (Ed) van, van der Velde, N., Polinder, S. (Suzanne), Mattace Raso, F.U.S. (Francesco), Hartholt, K.A. (Klaas), Boyé, N.D.A., Looman, C.W.N. (Caspar), Lips, P., Vries, O.J. (Oscar) de, and Kerver, A.J.H. (Albert J.H.)

Abstract

Objectives: to investigate the effect of withdrawal of fall-risk-increasing-drugs (FRIDs) versus 'care as usual' on reducing falls in community-dwelling older fallers. Design: randomised multicentre trial. Participants: six hundred and twelve older adults who visited an Emergency Department (ED) because of a fall. Interventions: withdrawal of FRIDs. Main Outcomes and Measures: primary outcome was time to the first self-reported fall. Secondary outcomes were time to the second self-reported fall and to falls requiring a general practitioner (GP)-consultation or ED-visit. Intention-to-treat (primary) and a per-protocol (secondary) analysis were conducted. The hazard ratios (HRs) for time-to-fall were calculated using a Cox-regression model. Differences in cumulative incidence of falls were analysed using Poisson regression. Results: during 12 months follow-up, 91 (34%) control and 115 (37%) intervention participants experienced a fall; 35% of all attempted interventions were unsuccessful, either due to recurrence of the initial indication for prescribing, additional medication for newly diagnosed conditions or non-compliance. Compared to baseline, the overall percentage of users of =3 FRIDs at 12 months did not change in either the intervention or the control group. Our intervention did not have a significant effect on time to first fall (HR 1.17; 95% confidence interval 0.89-1.54), time to second fall (1.19; 0.78-1.82), time to first fall-related GP-consultation (0.66; 0.42-1.06) or time to first fall-related ED-visit (0.85; 0.43-1.68). Conclusion: in this population of complex multimorbid patients visiting an ED because of a fall, our single intervention of FRIDs-withdrawal was not effective in reducing falls.

Published
2017
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3. 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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4. 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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5. Cost-utility of medication withdrawal in older fallers: results from the improving medication prescribing to reduce risk of FALLs (IMPROveFALL) trial

Author

Polinder, S. (Suzanne), Boyé, N.D.A. (Nicole), Mattace Raso, F.U.S. (Francesco), Velde, N. (Nathalie) van der, Hartholt, K.A. (Klaas), Vries, O.J. (Oscar) de, Lips, P. (Paul), Cammen, T.J.M. (Tischa) van der, Patka, P. (Peter), Beeck, E.F. (Ed) van, Lieshout, E.M.M. (Esther) van, Polinder, S. (Suzanne), Boyé, N.D.A. (Nicole), Mattace Raso, F.U.S. (Francesco), Velde, N. (Nathalie) van der, Hartholt, K.A. (Klaas), Vries, O.J. (Oscar) de, Lips, P. (Paul), Cammen, T.J.M. (Tischa) van der, Patka, P. (Peter), Beeck, E.F. (Ed) van, and Lieshout, E.M.M. (Esther) van

Abstract

Background: The use of Fall-Risk-Increasing-Drugs (FRIDs) has been associated with increased risk of falls and associated injuries. This study investigates the effect of withdrawal of FRIDs versus 'care as usual' on health-related quality of life (HRQoL), costs, and cost-utility in community-dwelling older fallers. Methods: In a prospective multicenter randomized controlled trial FRIDs assessment combined with FRIDs-withdrawal or modification was compared with 'care as usual' in older persons, who visited the emergency department after experiencing a fall. For the calculation of costs the direct medical costs (intramural and extramural) and indirect costs (travel costs) were collected for a 12 month period. HRQoL was measured at baseline and at 12 months follow-up using the EuroQol-5D and Short Form-12 version 2. The change in EuroQol-5D and Short Form-12 scores over 12 months follow-up within the control and intervention groups was compared using the Wilcoxon Signed Rank test for continuous variables and the McNemar test for dichotomous variables. The change in scores between the control and intervention groups were compared using a two-way analysis of variance. Results: We included 612 older persons who visited an emergency department because of a fall. The mean cost of the FRIDs intervention was €120 per patient. The total fall-related healthcare costs (without the intervention costs) did not differ significantly between the intervention group and the control group (€2204 versus €2285). However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant. Furthermore, the control group had a greater decline in EuroQol-5D utility score during the 12-months follow-up than the intervention group (p = 0.02). The change in the Short Form-12 Physical Component Summary and Mental Component Summary scores did not differ significantly between the two groups. Conclusions: Withdrawal of FRID's in older persons who visited an emergency department due

Published
2016
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6. 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
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7. 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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8. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Author

Reppe, S. (Sjur), Wang, Y. (Yunpeng), Thompson, W.K. (Wesley K.), McEvoy, L.K. (Linda K.), Schork, N.J. (Nicholas), Zuber, V. (Verena), Leblanc, M. (Marissa), Bettella, F. (Francesco), Mills, I.G. (Ian G.), Desikan, R.S. (Rahul S.), Djurovic, S. (Srdjan), Gautvik, K.M. (Kaare), Dale, A.M. (Anders), Andreassen, O.A. (Ole), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James F), Aalto, V. (Ville), Alen, M. (Markku), Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), Lacroix, A.Z. (Andrea Z.), Lee, S.H. (Seung Hun), Leung, P.C. (Ping C.), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, J. (Jean), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William D.), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.S.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan Th), Rotter, J.I. (Jerome I.), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S.R. (Steven R.), Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K.T., Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak Chung), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nicholas J.), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara B.), Kung, A.W.C. (Annie Wai Chee), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John P.A.), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Reppe, S. (Sjur), Wang, Y. (Yunpeng), Thompson, W.K. (Wesley K.), McEvoy, L.K. (Linda K.), Schork, N.J. (Nicholas), Zuber, V. (Verena), Leblanc, M. (Marissa), Bettella, F. (Francesco), Mills, I.G. (Ian G.), Desikan, R.S. (Rahul S.), Djurovic, S. (Srdjan), Gautvik, K.M. (Kaare), Dale, A.M. (Anders), Andreassen, O.A. (Ole), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James F), Aalto, V. (Ville), Alen, M. (Markku), Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), Lacroix, A.Z. (Andrea Z.), Lee, S.H. (Seung Hun), Leung, P.C. (Ping C.), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, J. (Jean), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William D.), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.S.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan Th), Rotter, J.I. (Jerome I.), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S.R. (Steven R.), Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K.T., Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak Chung), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nicholas J.), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara B.), Kung, A.W.C. (Annie Wai Chee), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John P.A.), Kiel, D.P. (Douglas P.), and Rivadeneira Ramirez, F. (Fernando)

Abstract

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Published
2015
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9. Primary human osteoblasts in response to 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3and 24R,25-dihydroxyvitamin D3

Author

Van Der Meijden, K. (Karen), Lips, P. (Paul), Driel, M. (Marjolein) van, Heijboer, M.P. (Rien), Schulten, E.A.J.M. (Engelbert A. J. M.), Heijer, M. (Martin) den, Bravenboer, N. (Nathalie), Van Der Meijden, K. (Karen), Lips, P. (Paul), Driel, M. (Marjolein) van, Heijboer, M.P. (Rien), Schulten, E.A.J.M. (Engelbert A. J. M.), Heijer, M. (Martin) den, and Bravenboer, N. (Nathalie)

Abstract

The most biologically active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has well known direct effects on osteoblast growth and differentiation in vitro. The precursor 25-hydroxyvitamin D3 (25(OH)D3) can affect osteoblast function via conversion to 1,25(OH)2D3, however, it is largely unknown whether 25(OH)D3 can affect primary osteoblast function on its own. Furthermore, 25(OH)D3 is not only converted to 1,25(OH)2D3, but also to 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) which may have bioactivity as well. Therefore we used a primary human osteoblast model to examine whether 25(OH)D3 itself can affect osteoblast function using CYP27B1 silencing and to investigate whether 24R,25(OH)2D3 can affect osteoblast function. We showed that primary human osteoblasts responded to both 25(OH)D3 and 1,25(OH)2D3 by reducing their proliferation and enhancing their differentiation by the increase of alkaline phosphatase, osteocalcin and osteopontin expression. Osteoblasts expressed CYP27B1 and CYP24 and synthesized 1,25(OH)2D3 and 24R,25(OH)2D3 dose-dependently. Silencing of CYP27B1 resulted in a decline of 1,25(OH)2D3 synthesis, but we observed no significant differences in mRNA levels of differentiation markers in CYP27B1-silenced cells compared to control cells after treatment with 25(OH)D3. We demonstrated that 24R,25(OH)2D3 increased mRNA levels of alkaline phosphatase, osteocalcin and osteopontin. In addition, 24R,25(OH)2D3 strongly increased CYP24 mRNA. In conclusion, the vitamin D metabolites 25(OH)D3, 1,25(OH)2D3 and 24R,25(OH)2D3 can affect osteoblast differentiation directly or indirectly. We showed that primary human osteoblasts not only respond to 1,25(OH)2D3, but also to 24R,25(OH)2D3 by enhancing osteoblast differentiation. This suggests that 25(OH)D3 can affect osteoblast differentiation via conversion to the active metabolite 1,25(OH)2D3, but also via conversion to 24R,25(OH)2D3. Whether 25(OH)D3 has direct actions on osteoblast function needs further investi

Published
2014
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10. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Author

Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), and Estrada Gil, K. (Karol)

Abstract

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Published
2014
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11. Radioactive iodine in the treatment of medullary thyroid carcinoma: A controlled multicenter study

Author

Meijer, J.A.A. (J. A A), Bakker, L.E.H. (Leontine), Valk, G.D. (Gerlof), Herder, W.W. (Wouter) de, Wilt, J.H.W. (Johannes) de, Netea-Maier, R.T. (Romana), Schaper, N., Fliers, E. (Eric), Lips, P. (Paul), Plukker, J.T. (John), Links, T.P. (Thera), Smit, J.A. (J.), Meijer, J.A.A. (J. A A), Bakker, L.E.H. (Leontine), Valk, G.D. (Gerlof), Herder, W.W. (Wouter) de, Wilt, J.H.W. (Johannes) de, Netea-Maier, R.T. (Romana), Schaper, N., Fliers, E. (Eric), Lips, P. (Paul), Plukker, J.T. (John), Links, T.P. (Thera), and Smit, J.A. (J.)

Abstract

Objective: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. Design: Retrospective multicenter study in eight University Medical Centers in The Netherlands. Methods: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. Results: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. Conclusions: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

Published
2013
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12. Vitamin D and physical performance in older men and women visiting the emergency department because of a fall: Data from the improving medication prescribing to reduce risk of FALLs (IMPROveFALL) study

Author

Boyé, N.D.A. (Nicole), Oudshoorn, C. (Christian), Velde, N. (Nathalie) van der, Lieshout, E.M.M. (Esther) van, Vries, O.J. (Oscar) de, Lips, P. (Paul), Beeck, E.F. (Ed) van, Patka, P. (Peter), Cammen, T.J.M. (Tischa) van der, Boyé, N.D.A. (Nicole), Oudshoorn, C. (Christian), Velde, N. (Nathalie) van der, Lieshout, E.M.M. (Esther) van, Vries, O.J. (Oscar) de, Lips, P. (Paul), Beeck, E.F. (Ed) van, Patka, P. (Peter), and Cammen, T.J.M. (Tischa) van der

Abstract

Objectives To investigate whether serum 25-hydroxy vitamin D (25(OH)D) is associated with physical performance in men and women. Design Cross-sectional. Setting Emergency departments (EDs) of five hospitals. Participants Older adults who visited an ED because of a fall (N = 616). Measurements Physical performance was assessed using the Timed Up and Go Test, the Five Time Sit to Stand Test, handgrip strength, and the tandem stand test. Multivariate linear regression was used to assess the association between physical performance and log-transformed 25(OH)D concentration adjusted for potential confounders. Results In men, higher serum 25(OH)D concentration was significantly associated with better handgrip strength (regression coefficient (B) = 3.86, 95% confidence interval (CI) = 2.04-5.69), faster TUG time (B = -2.82, 95% CI = -4.91 to -0.73), and faster FTSS time (B = -3.39, 95% CI = -5.67 to -1.11). In women, higher serum 25(OH)D concentration was significantly associated with faster TUG time (B = -2.68, 95% CI = -4.87 to -0.49). Conclusion A positive association was found between serum 25(OH)D level and physical performance in men and women. Intervention studies are needed of vitamin D-deficient older men and women to further investigate the effect

Published
2013
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13. High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease

Author

Manenschijn, L. (Laura), Schaap, L.A. (Laura), Schoor, N.M. (Natasja) van, Pas, S. (Suzan) van der, Peeters, G.M.E.E. (Geeske), Lips, P. (Paul), Koper, J.W. (Jan), Rossum, E.F.C. (Liesbeth) van, Manenschijn, L. (Laura), Schaap, L.A. (Laura), Schoor, N.M. (Natasja) van, Pas, S. (Suzan) van der, Peeters, G.M.E.E. (Geeske), Lips, P. (Paul), Koper, J.W. (Jan), and Rossum, E.F.C. (Liesbeth) van

Abstract

Background: Stress is associated with an increased incidence of cardiovascular disease. The impact of chronic stress on cardiovascular risk has been studied by measuring cortisol in serum and saliva, which are measurements of only 1 time point. These studies yielded inconclusive results. The measurement of cortisol in scalp hair is a novel method that provides the opportunity to measure long-term cortisol exposure. Our aim was to study whether long-term cortisol levels, measured in scalp hair, are associated with cardiovascular diseases. Methods: A group of 283 community-dwelling elderly participants were randomly selected from a large population-based cohort study (median age, 75 y; range, 65-85 y). Cortisol was measured in 3-cm hair segments, corresponding roughly with a period of 3 months. Self-reported data concerning coronary heart disease, stroke, peripheral arterial disease, diabetes mellitus, and other chronic noncardiovascular diseases were collected. Results: Hair cortisol levels were significantly lower in women than in men (21.0 vs 26.3 pg/mg hair; P < .001). High hair cortisol levels were associated with an increased cardiovascular risk (odds ratio, 2.7; P = .01) and an increased risk of type 2 diabetes mellitus (odds ratio, 3.2; P = .04). There were no associations between hair cortisol levels and noncardiovascular diseases. Conclusions: Elevated long-term cortisol levels are associated with a history of cardiovascular disease. The increased cardiovascular risk we found is equivalent to the effect of traditional cardiovascular risk factors, suggesting that long-term elevated cortisol may be an important cardiovascular risk factor. Copyright

Published
2013
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14. The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: A systematic review

Author

Krul-Poel, Y.H.M. (Y. H M), Snackey, C. (C.), Louwers, Y.V. (Yvonne), Lips, P. (Paul), Lambalk, C.B. (Cornelius), Laven, J.S.E. (Joop), Simsek, S. (S.), Krul-Poel, Y.H.M. (Y. H M), Snackey, C. (C.), Louwers, Y.V. (Yvonne), Lips, P. (Paul), Lambalk, C.B. (Cornelius), Laven, J.S.E. (Joop), and Simsek, S. (S.)

Abstract

Context: Metabolic disturbances, in particular, insulin resistance (IR) and dyslipidemia, are common in women suffering from polycystic ovary syndrome (PCOS). Evidence is accumulating that vitamin D status may contribute to the development of metabolic disturbances in PCOS. Objective: The aim of this study was to carry out a systematic review addressing the association between vitamin D status, vitamin D receptor polymorphisms, and/or polymorphisms related to vitamin D metabolism and metabolic disturbances in women with PCOS. Design and methods: A systematic search of electronic databases was carried out up to January 2013 for observational studies and clinical trials in women suffering from PCOS with outcome measures that were related to vitamin D status. We conducted univariate and multivariate regression analyses of the weighted means to gain insights into the association between vitamin D, BMI, and IR based on existing literature. Results: We found 29 eligible trials with inconsistency in their results. One well-designed randomized controlled trial has been carried out until now. Univariate regression analyses of the weighted means revealed vitamin D to be a significant and independent predictor of IR in both PCOS and control women. The significance disappeared after adjustment for BMI in PCOS women. Conclusions: Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. The causal relationship between vitamin D status and metabolic disturbances in PCOS remains to be determined in well-designed placebo-controlled randomized clinical trials.

Published
2013
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15. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Author

Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James), Aalto, V. (Ville), Alen, T.A. (Theo) van, Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), LaCroix, A.Z. (Andrea), Lee, S.U. (Seung), Leung, P.C. (Ping), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, M.M. (Margaret M.), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan), Reppe, S. (Sjur), Rotter, J.I. (Jerome), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Gautvik, K.M. (Kaare), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S., Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K-T. (Kay-Tee), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara), Kung, A.W.C. (Annie), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James), Aalto, V. (Ville), Alen, T.A. (Theo) van, Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), LaCroix, A.Z. (Andrea), Lee, S.U. (Seung), Leung, P.C. (Ping), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, M.M. (Margaret M.), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan), Reppe, S. (Sjur), Rotter, J.I. (Jerome), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Gautvik, K.M. (Kaare), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S., Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K-T. (Kay-Tee), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara), Kung, A.W.C. (Annie), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), and Rivadeneira Ramirez, F. (Fernando)

Abstract

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10 -8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10 -4, Bonferroni corrected), of which six reached P < 5 × 10 -8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Published
2012
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16. [Cost] effectiveness of withdrawal of fall-risk increasing drugs versus conservative treatment in older fallers: Design of a multicenter randomized controlled trial (IMPROveFALL-study)

Author

Hartholt, K.A. (Klaas), Velde, N. (Nathalie) van der, Lieshout, E.M.M. (Esther) van, Polinder, S. (Suzanne), Vries, O.J. (Oscar) de, Boyé, N.D.A. (Nicole), Kerver, A.L.A. (Anton), Ziere, G. (Gijsbertus), Bruijninckx, M.M.M. (Milko), Mattace Raso, F.U.S. (Francesco), Uitterlinden, A.G. (André), Beeck, E.F. (Ed) van, Lips, P. (Paul), Patka, P. (Peter), Cammen, T.J.M. (Tischa) van der, Hartholt, K.A. (Klaas), Velde, N. (Nathalie) van der, Lieshout, E.M.M. (Esther) van, Polinder, S. (Suzanne), Vries, O.J. (Oscar) de, Boyé, N.D.A. (Nicole), Kerver, A.L.A. (Anton), Ziere, G. (Gijsbertus), Bruijninckx, M.M.M. (Milko), Mattace Raso, F.U.S. (Francesco), Uitterlinden, A.G. (André), Beeck, E.F. (Ed) van, Lips, P. (Paul), Patka, P. (Peter), and Cammen, T.J.M. (Tischa) van der

Abstract

Background: Fall incidents represent an increasing public health problem in aging societies worldwide. A major risk factor for falls is the use of fall-risk increasing drugs. The primary aim of the study is to compare the effect of a structured medication assessment including the withdrawal of fall-risk increasing drugs on the number of new falls versus 'care as usual' in older adults presenting at the Emergency Department after a fall. Methods/Design. A prospective, multi-center, randomized controlled trial will be conducted in hospitals in the Netherlands. Persons aged 65 years who visit the Emergency Department due to a fall are invited to participate in this trial. All patients receive a full geriatric assessment at the research outpatient clinic. Patients are randomized between a structured medication assessment including withdrawal of fall-risk increasing drugs and 'care as usual'. A 3-monthly falls calendar is used for assessing the number of falls, fallers and associated injuries over a one-year follow-up period. Measurements will be at three, six, nine, and twelve months and include functional outcome, healthcare consumption, socio-demographic characteristics, and clinical information. After twelve months a second visit to the research outpatient clinic will be performed, and adherence to the new medication regimen in the intervention group will be measured. The primary outcome will be the incidence of new falls. Secondary outcome measurements are possible health effects of medication withdrawal, health-related quality of life (Short Form-12 and EuroQol-5D), costs, and cost-effectiveness of the intervention. Data will be analyzed using an intention-to-treat analysis. Discussion. The successful completion of this trial will provide evidence on the effectiveness of withdrawal of fall-risk increasing drugs in older patients as a method for falls reduction. Trial Registration. The trial is registered in the Netherlands Trial Register (NTR1593).

Published
2011
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17. 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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18. Is there a U-shaped association between physical activity and falling in older persons?

Author

Peeters, G.M.E.E. (Geeske), Schoor, N.M. (Natasja) van, Pluijm, S.M.F. (Saskia), Deeg, D.J.H. (Dorly), Lips, P. (Paul), Peeters, G.M.E.E. (Geeske), Schoor, N.M. (Natasja) van, Pluijm, S.M.F. (Saskia), Deeg, D.J.H. (Dorly), and Lips, P. (Paul)

Abstract

Summary: This study tests whether the relationship between physical activity and (recurrent) falling is U-shaped. Among 1,337 community-dwelling older persons, no evidence for a nonlinear association was found. If all older persons increase their physical activity level with 100 units, 4% may be prevented to become recurrent fallers. Introduction: Previous studies suggest a U-shaped relationship between physical activity and falling. This study tests this hypothesis and examines whether this relationship is modified by level of physical functioning. Methods: Community-dwelling persons (65+) from the Longitudinal Aging Study Amsterdam (LASA) were prospectively followed on falls for 3 years after baseline assessment in 1995/1996 (n = 1,337). Outcome measures were time to first fall and time to recurrent falling. The LASA Physical Activity Questionnaire was used to calculate physical activity in minutes per day weighted for intensity (range 0-2000). Physical functioning was measured with physical performance tests and self reported functional limitations. Confounders were age, sex, body mass index, chronic diseases, psychotropic medication, cognitive functioning, depressive symptoms, and fear of falling. Results: No evidence for a nonlinear association was found (p for physical activity2> 0.20). No significant association was found between physical activity and time to first fall. An increase in physical activity of 100 units led to a 4% decrease in risk of recurrent falling (adjusted hazard ratio 0.96, 95% c

Published
2010
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19. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation

Author

Estrada Gil, K. (Karol), Krawczak, M. (Michael), Schreiber, S. (Stefan), Duijn, K. (Kate) van, Stolk, L. (Lisette), Meurs, J.B.J. (Joyce) van, Liu, F. (Fan), Penninx, B.W.J.H. (Brenda), Smit, J.H. (Jan), Vogelzangs, N. (Nicole), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Lorentzon, M. (Mattias), Eller-Eberstein, H. (Huberta) von, Lips, P. (Paul), Schoor, N. (Natascha), Pop, V.J.M. (Victor), Keijzer, J. (Jules) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Oostra, B.A. (Ben), Ohlsson, C. (Claes), Boomsma, D.I. (Dorret), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Kayser, M.H. (Manfred), Estrada Gil, K. (Karol), Krawczak, M. (Michael), Schreiber, S. (Stefan), Duijn, K. (Kate) van, Stolk, L. (Lisette), Meurs, J.B.J. (Joyce) van, Liu, F. (Fan), Penninx, B.W.J.H. (Brenda), Smit, J.H. (Jan), Vogelzangs, N. (Nicole), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Lorentzon, M. (Mattias), Eller-Eberstein, H. (Huberta) von, Lips, P. (Paul), Schoor, N. (Natascha), Pop, V.J.M. (Victor), Keijzer, J. (Jules) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Oostra, B.A. (Ben), Ohlsson, C. (Claes), Boomsma, D.I. (Dorret), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), and Kayser, M.H. (Manfred)

Abstract

Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (Pcombined= 3.4 × 10-9). Notably, a second SNP (rs6718438) located ∼450 bp away and in strong LD (r2= 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (Pcombined= 2.1 × 10-7). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.

Published
2009
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20. Loci at chromosomes 13, 19 and 20 influence age at natural menopause

Author

Stolk, L. (Lisette), Zhai, G. (Guangju), Meurs, J.B.J. (Joyce) van, Verbiest, M.M.P.J. (Michael), Visser, J.A. (Jenny), Estrada Gil, K. (Karol), Rivadeneira Ramirez, F. (Fernando), Williams, F.M. (Frances), Cherkas, L. (Lynn), Deloukas, P. (Panagiotis), Soranzo, N. (Nicole), Keyzer, J.J. (Jules) de, Pop, V.J.M. (Victor), Lips, P. (Paul), Lebrun, C.E.I. (Corinne), Schouw, Y.T. (Yvonne) van der, Grobbee, D.E. (Diederick), Witteman, J.C.M. (Jacqueline), Hofman, A. (Albert), Pols, H.A.P. (Huib), Laven, J.S.E. (Joop), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Stolk, L. (Lisette), Zhai, G. (Guangju), Meurs, J.B.J. (Joyce) van, Verbiest, M.M.P.J. (Michael), Visser, J.A. (Jenny), Estrada Gil, K. (Karol), Rivadeneira Ramirez, F. (Fernando), Williams, F.M. (Frances), Cherkas, L. (Lynn), Deloukas, P. (Panagiotis), Soranzo, N. (Nicole), Keyzer, J.J. (Jules) de, Pop, V.J.M. (Victor), Lips, P. (Paul), Lebrun, C.E.I. (Corinne), Schouw, Y.T. (Yvonne) van der, Grobbee, D.E. (Diederick), Witteman, J.C.M. (Jacqueline), Hofman, A. (Albert), Pols, H.A.P. (Huib), Laven, J.S.E. (Joop), Spector, T.D. (Timothy), and Uitterlinden, A.G. (André)

Abstract

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10 11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10 11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10 8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Published
2009
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21. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis

Author

Meurs, J.B.J. (Joyce) van, Trikalinos, T.A. (Thomas), Ralston, S.H. (Stuart), Balcells, S. (Susana), Brandi, M.L., Brixen, K. (Kim), Kiel, D.P. (Douglas), Langdahl, B.L. (Bente), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Obermayer-Pietsch, B. (Barbara), Ohlsson, C. (Claes), Pettersson, U. (Ulrika), Reid, D.M. (David), Rousseau, M.F. (Francois), Scollen, S. (Serena), Van Hul, W. (Wim), Agueda, L. (Lidia), Åkesson, K. (Kristina), Benevolenskaya, L.I. (Lidia), Ferrari, S.L. (Serge), Hallmans, G. (Göran), Hofman, A. (Albert), Husted, L.B. (Lise Bjerre), Kruk, M. (Marcin), Kaptoge, S. (Stephen), Karasik, D. (David), Karlsson, M. (Magnus), Lorentzon, M. (Mattias), Masi, L. (Laura), McGuigan, F.E., Mellström, D. (Dan), Mosekilde, L. (Leif), Nogues, X. (Xavier), Pols, H.A.P. (Huib), Reeve, J. (Jonathan), Renner, W. (Wilfried), Rivadeneira Ramirez, F. (Fernando), Schoor, N.M. (Natasja) van, Weber, K. (Kurt), Ioannidis, J.P.A. (John), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Trikalinos, T.A. (Thomas), Ralston, S.H. (Stuart), Balcells, S. (Susana), Brandi, M.L., Brixen, K. (Kim), Kiel, D.P. (Douglas), Langdahl, B.L. (Bente), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Obermayer-Pietsch, B. (Barbara), Ohlsson, C. (Claes), Pettersson, U. (Ulrika), Reid, D.M. (David), Rousseau, M.F. (Francois), Scollen, S. (Serena), Van Hul, W. (Wim), Agueda, L. (Lidia), Åkesson, K. (Kristina), Benevolenskaya, L.I. (Lidia), Ferrari, S.L. (Serge), Hallmans, G. (Göran), Hofman, A. (Albert), Husted, L.B. (Lise Bjerre), Kruk, M. (Marcin), Kaptoge, S. (Stephen), Karasik, D. (David), Karlsson, M. (Magnus), Lorentzon, M. (Mattias), Masi, L. (Laura), McGuigan, F.E., Mellström, D. (Dan), Mosekilde, L. (Leif), Nogues, X. (Xavier), Pols, H.A.P. (Huib), Reeve, J. (Jonathan), Renner, W. (Wilfried), Rivadeneira Ramirez, F. (Fernando), Schoor, N.M. (Natasja) van, Weber, K. (Kurt), Ioannidis, J.P.A. (John), and Uitterlinden, A.G. (André)

Abstract

Context: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. Objective: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. Design and Setting: Prospective, multicenter, collaborative study of individuallevel data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. Main Outcome Measures: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. Results: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n=25 052 [number of participants with available data]; 20-mg/cm2lower BMD per Met667 allele copy; P=3.3 × 10-8), as was the Val1330 allele (n=24 812; 14-mg/cm2lower BMD per Val1330 copy; P=2.6 × 10-9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2(P=3.8 × 10-5) and 8 mg/cm2(P=5.0 × 10-6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fract

Published
2008
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22. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity

Author

Kevenaar, M.E. (Marlies), Themmen, A.P.N. (Axel), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Laven, J.S.E. (Joop), Schoor, N.M. (Natasja) van, Lips, P. (Paul), Pols, H.A.P. (Huib), Visser, J.A. (Jenny), Kevenaar, M.E. (Marlies), Themmen, A.P.N. (Axel), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Laven, J.S.E. (Joop), Schoor, N.M. (Natasja) van, Lips, P. (Paul), Pols, H.A.P. (Huib), and Visser, J.A. (Jenny)

Abstract

Background: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. Methods: In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. Results: The AMH Ile49Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). Conclusions: The observed association of the AMHR2 -482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.

Published
2007
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23. Vitamin D status in relation to one-year risk of recurrent falling in older men and women

Author

Snijder, M.B. (Marieke), Schoor, N.M. (Natasja) van, Pluijm, S.M.F. (Saskia), Dam, R.M. (Rob) van, Visser, M. (Marjolein), Lips, P. (Paul), Snijder, M.B. (Marieke), Schoor, N.M. (Natasja) van, Pluijm, S.M.F. (Saskia), Dam, R.M. (Rob) van, Visser, M. (Marjolein), and Lips, P. (Paul)

Abstract

Background: Falls frequently occur in the elderly and are a major cause of morbidity and mortality. Objective: The objective of the study was to prospectively investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and risk of recurrent falling in older men and women. Design: This was a prospective cohort study. Setting: An age- and sex-stratified random sample of the Dutch older population was determined. Subjects: Subjects included 1231 men and women (aged 65 yr and older) participating in the Longitudinal Aging Study Amsterdam. Measurements: Baseline serum 25(OH)D was determined by a competitive protein binding assay. During 1 yr, falls were prospectively recorded by means of a fall calendar. Results: Low 25(OH)D (<10 ng/ml) was associated with an increased risk of falling. After adjustment for age, sex, education level, region, season, physical activity, smoking, and alcohol intake, the odds ratios (95% confidence interval) were 1.78 (1.06-2.99) for subjects who experienced two falls or more as compared with those who did not fall or fell once and 2.23 (1.17-4.25) for subjects who fell three or more times as compared with those who fell two times or less. There was a statistically significant effect modification by age, and stratified analyses (<75 and ≥ 75 yr) showed that the associations were particularly strong in the younger age group; the odds ratios (95% confidence interval) were 5.21 (2.03-13.40) for two falls or more and 4.96 (1.52-16.23) for three falls or more. Conclusions: Poor vitamin D status is independently associated with an increased risk of falling in the elderly, particularly in those aged 65-75 yr. Copyright

Published
2006
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24. Large-scale evidence for the effect of the COLIA1 Sp1 Polymorphism on Osteoporosis Outcomes: The GENOMOS study

Author

Ralston, S.H. (Stuart), Uitterlinden, A.G. (André), Brandi, M.L., Balcells, S. (Susana), Langdahl, B.L. (Bente), Lips, P. (Paul), Lorenc, R. (Roman), Obermayer-Pietsch, B. (Barbara), Scollen, S. (Serena), Bustamante, M. (Mariona), Husted, L.B. (Lise Bjerre), Carey, A. (Alisoun), Diez-Perez, A. (Adolfo), Dunning, A.M. (Alison), Falchetti, A., Karczmarewicz, E. (Elzbieta), Kruk, M. (Marcin), Leeuwen, J.P.T.M. (Hans) van, Meurs, J.B.J. (Joyce) van, Mangion, J. (Jon), McGuigan, F.E., Mellibovsky, L. (Leonardo), Del Monte, F. (Francesca), Pols, H.A.P. (Huib), Reeve, J. (Jonathan), Reid, D.M. (David), Renner, W. (Wilfried), Rivadeneira Ramirez, F. (Fernando), Schoor, N.M. (Natasja) van, Sherlock, J.K. (Jon), Ioannidis, J.P.A. (John), Ralston, S.H. (Stuart), Uitterlinden, A.G. (André), Brandi, M.L., Balcells, S. (Susana), Langdahl, B.L. (Bente), Lips, P. (Paul), Lorenc, R. (Roman), Obermayer-Pietsch, B. (Barbara), Scollen, S. (Serena), Bustamante, M. (Mariona), Husted, L.B. (Lise Bjerre), Carey, A. (Alisoun), Diez-Perez, A. (Adolfo), Dunning, A.M. (Alison), Falchetti, A., Karczmarewicz, E. (Elzbieta), Kruk, M. (Marcin), Leeuwen, J.P.T.M. (Hans) van, Meurs, J.B.J. (Joyce) van, Mangion, J. (Jon), McGuigan, F.E., Mellibovsky, L. (Leonardo), Del Monte, F. (Francesca), Pols, H.A.P. (Huib), Reeve, J. (Jonathan), Reid, D.M. (David), Renner, W. (Wilfried), Rivadeneira Ramirez, F. (Fernando), Schoor, N.M. (Natasja) van, Sherlock, J.K. (Jon), and Ioannidis, J.P.A. (John)

Abstract

Background: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COL

Published
2006
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25. Homocysteine levels and the risk of osteoporotic fracture

Author

Meurs, J.B.J. (Joyce) van, Jonge, R. (Robert) de, Lindemans, J. (Jan), Groot, L.C.P.G.M. (Lisette) de, Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Pols, H.A.P. (Huib), Lips, P. (Paul), Breteler, M.M.B. (Monique), Dhonukshe-Rutten, R.A., Pluijm, S.M.F. (Saskia), Klift, M. (Marjolein) van der, Leeuwen, J.P.T.M. (Hans) van, Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Jonge, R. (Robert) de, Lindemans, J. (Jan), Groot, L.C.P.G.M. (Lisette) de, Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Pols, H.A.P. (Huib), Lips, P. (Paul), Breteler, M.M.B. (Monique), Dhonukshe-Rutten, R.A., Pluijm, S.M.F. (Saskia), Klift, M. (Marjolein) van der, Leeuwen, J.P.T.M. (Hans) van, and Hofman, A. (Albert)

Abstract

BACKGROUND: Very high plasma homocysteine levels are characteristic of homocystinuria, a rare autosomal recessive disease accompanied by the early onset of generalized osteoporosis. We therefore hypothesized that mildly elevated homocysteine levels might be related to age-related osteoporotic fractures. METHODS: We studied the association between circulating homocysteine levels and the risk of incident osteoporotic fracture in 2406 subjects, 55 years of age or older, who participated in two separate prospective, population-based studies. In the Rotterdam Study, there were two independent cohorts: 562 subjects in cohort 1, with a mean follow-up period of 8.1 years; and 553 subjects in cohort 2, with a mean follow-up period of 5.7 years. In the Longitudinal Aging Study Amsterdam, there was a single cohort of 1291 subjects, with a mean follow-up period of 2.7 years. Multivariate Cox proportional-hazards regression model

Published
2004

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