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The Association between Common Vitamin D Receptor Gene Variations and Osteoporosis: A Participant-Level Meta-Analysis

André G. Uitterlinden, PhD; Stuart H. Ralston, MD; Maria Luisa Brandi, MD, PhD; Alisoun H. Carey, PhD; Daniel Grinberg, PhD; Bente L. Langdahl, MD, PhD; Paul Lips, MD, PhD; Roman Lorenc, MD, PhD; Barbara Obermayer-Pietsch, MD; Jonathan Reeve, DM, DSc; David M. Reid, MD; Antonietta Amedei, MD; Amelia Bassiti, MSc; Mariona Bustamante, BSc; Lise Bjerre Husted, PhD; Adolfo Diez-Perez, MD, PhD; Harald Dobnig, MD; Alison M. Dunning, PhD; Anna Enjuanes, PhD; Astrid Fahrleitner-Pammer, MD; Yue Fang, PhD; Elzbieta Karczmarewicz, PhD; Marcin Kruk, PhD; Johannes P.T.M. van Leeuwen, PhD; Carmelo Mavilia, PhD; Joyce B.J. van Meurs, PhD; Jon Mangion, PhD; Fiona E.A. McGuigan, PhD; Huibert A.P. Pols, MD, PhD; Wilfried Renner, PhD; Fernando Rivadeneira, MD, PhD; Natasja M. van Schoor, PhD; Serena Scollen, BSc; Rachael E. Sherlock, BSc; John P.A. Ioannidis, MD; APOSS Investigators; EPOS Investigators; EPOLOS Investigators; FAMOS Investigators; LASA Investigators; Rotterdam Study Investigators, GENOMOS Study*
[+] Article and Author Information

From Erasmus MC, Rotterdam, the Netherlands; University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; University of Aberdeen Medical School, Aberdeen, United Kingdom; Oxagen Limited, Abingdon, United Kingdom; University of Florence, Florence, Italy; University of Barcelona, Barcelona, Spain; Aarhus University Hospital, Aarhus, Denmark; The Children's Memorial Health Institute, Warsaw, Poland; Medical University, Graz, Austria; Strangeways Research Laboratory, Cambridge University, Cambridge, United Kingdom; Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, the Netherlands; Hospital del Mar–IMIM, Autonomous University Barcelona, Barcelona, Spain; and University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology–Hellas, Ioannina, Greece.


Grant Support: By the European Commission (grant QLK6-CT-2002-02629). EPOS was financially supported by a European Union Concerted Action Grant under Biomed-1 (BMH1CT920182) and European Union grants C1PDCT925102, ERBC1PDCT 930105, and 940229; the central coordination was also supported by the UK Arthritis Research Campaign, the Medical Research Council (G9321536), and the European Foundation for Osteoporosis and Bone Disease. The European Union's PECO program linked to BIOMED 1 funded in part the participation of the Budapest, Prague, Piestany, Szczecin, and Moscow centers; data collection from Zagreb was supported by a grant from the Wellcome Trust, and the central radiograph evaluation was generously sponsored by the Bundesministerium fur Forschung and Technologie, Germany. The remaining funding was provided by or through the following centers: Radiological Evaluation: Department of Radiology and Nuclear Medicine, Free University, Berlin, Germany (D. Felsenberg, W. Gowin, G. Armbrecht); Participating Investigative Centers: Institute of Rheumatology, Moscow, Russia (L.I. Benevolenskaya); Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom (A. Bhalla); Hospital de Angra do Herismo, Azores, Portugal (J. Bruges Armas); Asturias General Hospital, Oviedo, Spain (J.B. Cannata Andia and M. Naves Diaz); University Hospital, Leuven, Belgium (S. Boonen); Charles University, Prague, Czech Republic (J.J. Stepan); Zagreb, Croatia (I. Jajic); Hospital de San Joao, Oporto, Portugal (A. Lopes Vaz); University of Athens, Greece (G. Lyritis); Institute of Rheumatic Diseases, Piestany, Slovakia (P. Masaryk); Academy of Medicine, Szczecin, Poland (T. Miazgowski); University of Siena, Siena, Italy (R. Nuti); National Institute of Rheumatology and Physiotherapy, Budapest, Hungary (G. Poor); and University Hospital, Graz, Austria (K. Weber). The Longitudinal Aging Study Amsterdam is funded by the Ministry of Health, Welfare and Sports of the Netherlands.

Potential Financial Conflicts of Interest: Consultancies: P. Lips (Merck & Co. Inc., Eli Lilly Inc., Wyeth, Novartis); Honoraria: P. Lips (Merck & Co. Inc., Eli Lilly Inc., Wyeth, Novartis, Servier); Expert testimony: P. Lips (Eli Lilly Inc.); Grants received: A.G. Uitterlinden (European Union), S.H. Ralston (European Union), P. Lips (Eli Lilly Inc., Merck & Co. Inc., Aventis, Wyeth); Patents received: A.G. Uitterlinden (Erasmus University Rotterdam), S.H. Ralston (University of Aberdeen); J.P.T.M. van Leeuwen (Erasmus University Rotterdam), H.A.P. Pols (Erasmus University Rotterdam).

Requests for Single Reprints: John P.A. Ioannidis, MD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece; e-mail, jioannid@cc.uoi.gr.

Current Author Addresses: Drs. Uitterlinden, Fang, van Leeuwen, van Meurs, Pols, and Rivadeneira: Department of Internal Medicine, Erasmus MC, 50 Dr. Molewaterplein, NL-3015 GE Rotterdam, The Netherlands.

Dr. Ralston: Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XN, United Kingdom.

Drs. Brandi, Amedei, and Mavilia: Department of Internal Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

Drs. Carey and Mangion and Ms. Sherlock: Oxagen Limited, 91 Milton Park, Abingdon, Oxon OX14 4RY, United Kingdom.

Dr. Grinberg and Ms. Bustamante: Department of Genetics, University of Barcelona, Avenue Digonal 645, E-08028 Barcelona, Spain.

Drs. Langdahl and Husted: Department of Endocrinology, Aarhus University Hospital, Tage-Hansens Gadez, C DK-8000 Aarhus, Denmark.

Drs. Lips and van Schoor: Institute for Research in Extramural Medicine, VU University Medical Center, Vd. Boechorststr. 7, 1081 BT Amsterdam, the Netherlands.

Drs. Lorenc, Karczmarewicz, and Kruk: Department of Biochemistry and Experimental Medicine, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-930 Warsaw, Poland.

Drs. Obermayer-Pietsch, Dobnig, Fahrleitner-Pammer, and Renner: Department of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University, Auenbruggerplatz 15, A-8026 GR12 Graz, Austria.

Drs. Reeve and Dunning and Ms. Scollen: Strangeways Research Laboratory, Cambridge University, Worts Causeway, Cambridge CB1 8RN, United Kingdom.

Drs. Reid and McGuigan and Ms. Bassiti: Department of Medicine and Therapeutics, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.

Drs. Diez-Perez and Enjuanes: Hospital del Mar-IMIM, Autonomous University Barcelona, P. Maritim 25-29, 08003 Barcelona, Spain.

Dr. Ioannidis: Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology–Hellas, 45110 Ioannina, Greece.

Author Contributions: Conception and design: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, P. Lips, R. Lorenc, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Amedei, A. Bassiti, M. Bustamante, L.B. Husted, A. Diez-Perez, H. Dobnig, A.M. Dunning, A. Enjuanes, A. Fahrleitner-Pammer, E. Karczmarewicz, M. Kruk, C. Mavilia, J. Mangion, F.E.A. McGuigan, H.A.P. Pols, W. Renner, F. Rivadeneira, N.M. van Schoor, S. Scollen, R.E. Sherlock, J.P.A. Ioannidis.

Analysis and interpretation of the data: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, P. Lips, R. Lorenc, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Amedei, A. Bassiti, M. Bustamante, L.B. Husted, H. Dobnig, A.M. Dunning, A. Enjuanes, A. Fahrleitner-Pammer, Y. Fang, E. Karczmarewicz, M. Kruk, J.P.T.M. van Leeuwen, C. Mavilia, J.B.J. van Meurs, J. Mangion, F.E.A. McGuigan, H.A.P. Pols, W. Renner, F. Rivadeneira, N.M. van Schoor, S. Scollen, R.E. Sherlock, J.P.A. Ioannidis.

Drafting of the article: A.G. Uitterlinden, S.H. Ralston, J.P.A. Ioannidis.

Critical revision of the article for important intellectual content: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, P. Lips, R. Lorenc, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Amedei, A. Bassiti, M. Bustamante, L.B. Husted, A. Diez-Perez, H. Dobnig, A.M. Dunning, A. Enjuanes, A. Fahrleitner-Pammer, Y. Fang, E. Karczmarewicz, M. Kruk, J.P.T.M. van Leeuwen, C. Mavilia, J.B.J. van Meurs, J. Mangion, F.E.A. McGuigan, H.A.P. Pols, W. Renner, F. Rivadeneira, N.M. van Schoor, S. Scollen, R.E. Sherlock, J.P.A. Ioannidis.

Final approval of the article: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, P. Lips, R. Lorenc, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Amedei, A. Bassiti, M. Bustamante, L.B. Husted, A. Diez-Perez, H. Dobnig, A.M. Dunning, A. Enjuanes, A. Fahrleitner-Pammer, Y. Fang, E. Karczmarewicz, M. Kruk, J.P.T.M. van Leeuwen, C. Mavilia, J.B.J. van Meurs, J. Mangion, F.E.A. McGuigan, H.A.P. Pols, W. Renner, F. Rivadeneira, N.M. van Schoor, S. Scollen, R.E. Sherlock, J.P.A. Ioannidis.

Provision of study materials or patients: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, B.L. Langdahl, P. Lips, R. Lorenc, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Amedei, A. Diez-Perez, H. Dobnig, A. Fahrleitner-Pammer, Y. Fang, E. Karczmarewicz, M. Kruk, H.A.P. Pols, W. Renner, F. Rivadeneira.

Statistical expertise: J.B.J. van Meurs, J.P.A. Ioannidis.

Obtaining of funding: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, P. Lips, R. Lorenc, J. Reeve, D.M. Reid, H.A.P. Pols, J.P.A. Ioannidis.

Administrative, technical, or logistic support: A.G. Uitterlinden, J. Reeve, A. Bassiti, F.E.A. McGuigan, S. Scollen.

Collection and assembly of data: A.G. Uitterlinden, S.H. Ralston, M.L. Brandi, A.H. Carey, D. Grinberg, B.L. Langdahl, B. Obermayer-Pietsch, J. Reeve, D.M. Reid, A. Bassiti, M. Bustamante, L.B. Husted, A. Diez-Perez, A. Fahrleitner-Pammer, Y. Fang, E. Karczmarewicz, M. Kruk, J.B.J. van Meurs, J. Mangion, F.E.A. McGuigan, H.A.P. Pols, W. Renner, F. Rivadeneira, S. Scollen.


Ann Intern Med. 2006;145(4):255-264. doi:10.7326/0003-4819-145-4-200608150-00005
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The Genetic Markers for Osteoporosis (GENOMOS) consortium (9) performed a collaborative analysis that included 26 242 participants enrolled from 9 European teams. The consortium used prospective genotyping with cross-center standardization. Main outcomes were BMD at the lumbar spine and femoral neck, all fractures, and vertebral fractures.

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Figures

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Figure 1.
Differences in bone mineral density for recessive models for Cdx2 (A), Fok I (B), and haplotypes 1 (C) and 2 (D) of BsmI–ApaI–TaqI.

For each study, the point estimates and 95% CIs for the differences in bone mineral density in the lumbar spine (solid circles) and femoral neck (open circles) are shown. The study teams are listed alphabetically: 1 = Aarhus; 2 = Aberdeen; 3 = Amsterdam; 4 = Barcelona; 5 = European Prospective Osteoporosis Study (EPOS); 6 = Florence; 7 = Graz; 8 = Oxagen; and 9 = Rotterdam. Summary estimates of the differences and their CIs are given by inverse-variance random-effects models for female (Sum–F), male (Sum–M), and all participants (Total). Fixed-effects estimates are very similar (not shown). There is some between-study heterogeneity in the Cdx2 analysis for bone mineral density at the femoral neck (P = 0.002; I= 54%); otherwise no significant between-study heterogeneity is seen for any other comparison and skeletal site. None of the contrasts shown in the total summary exceed 7 mg/cm2 in bone mineral density differences. The primary analyses considering all genotypes and haplotype frequencies separately are summarized in Table 1 and Table 2. The European Polish Osteoporosis Study (EPOLOS) data are combined with the EPOS data. F = female; M = male.

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Figure 2.
Odds ratio for fractures in co-dominant models (per allele) for fracture at any site for Cdx2, FokI, and haplotypes 1 and 2 of BsmI–ApaI–TaqI.

Point estimates and 95% CIs are shown for the odds ratio in each study. Summary estimates of the odds ratios and their 95% CIs are given by random-effects (DerSimonian–Laird) models per sex and for the total database. Fixed-effects estimates are very similar (not shown). European Polish Osteoporosis Study (EPOLOS) data are combined with European Prospective Osteoporosis Study (EPOS) data.

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Appendix Figure.
Odds ratio for vertebral fractures for the Cdx2 polymorphism according to the dominant genetic model.
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