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

15 August 2006 | Volume 145 Issue 4 | Pages 255-264

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.

Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures.

Design: Prospective multicenter large-scale association study.

Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.

Participants: 26 242 participants (18 405 women).

Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.

Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm² for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).

Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.

Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

*For a list of study investigators, see the Appendix.

Editors' Notes Context Some studies suggest that multiple polymorphisms of the vitamin D receptor (VDR) gene influence regulation of bone mineral density (BMD). Contribution This multicenter, prospective study involving 26 242 participants examined associations between VDR polymorphisms (Cdx2-promoter, FokI, BsmI, ApaI, and TaqI) and BMD and fractures. These polymorphisms were not associated with lumbar spine or femoral neck BMD. Only the Cdx2 A-allele was associated with reduced risk for vertebral fracture. Cautions The study did not examine all VDR polymorphisms. Implications Contrary to previous claims, the FokI, BsmI, ApaI, and TaqI polymorphisms probably do not affect BMD or fracture risk. —The Editors

 

Author and Article 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{at}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.