The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis

André G. Uitterlinden, Stuart H. Ralston, Maria Luisa Brandi, Alisoun H. Carey, Daniel Grinberg, Bente L. Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsxch, Jonathan Reeve, David M. Reid, Antonietta Amedei, Amelia Bassiti, Mariona Bustamante, Lise Bjerre Husted, Adolfo Diez-Perez, Harald Dobnig, Alison M. Dunning, Anna Enjuanes, Astrid Fahrleitner-PammerYue Fang, Elzbieta Karczmarewicz, Marcin Kruk, Johannes P T M Van Leeuwen, Carmelo Mavilia, Joyce B J Van Meurs, Jon Mangion, Fiona E A McGuigan, Huibert A P Pols, Wilfried Renner, Fernando Rivadeneira, Natasja M. Van Schoor, Serena Scollen, Rachael E. Sherlock, John P A Ioannidis, Claire Parsons, Stuart Bear, Rosie Farmer, J. Lukaszkiewicz, P. Bilinski, E. Czerwinski, A. Lewinski, E. Marcinowska-Suchowierska, A. Milewicz, M. Spaczynski, M. Jaworski, R. Nuti, S. Grazio, T. Miazgowski, R. Boonen, P. Masaryk, J. J. Stepan, A. Lopes Vaz, J. Cannata, K. Weber, L. I. Benevolenskaya, C. Todd, K. T. Khaw, J. Da Silva, A. Bhalla, G. Poór, J. Bruges Armas, G. Lyritis, T. W. O'Neill, M. Lunt, Juliet Compston, Cyrus Cooper, Emma Duncan, Richard Keen, Alastair McLellan, John Wass, Ebbo Dekema, Huub Van Essen, Saskia Pluijm, Natalie Bravenboer, Albert Hofman, Cornelia M. Van Duijn, Paulus J. De Jong, Monique M. Breteler, Bruno H. Stricker, Jacqueline C. Witteman

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Abstract

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.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
JournalAnnals of Internal Medicine
Volume145
Issue number4
Publication statusPublished - Aug 15 2006

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Calcitriol Receptors
Bone Density
Osteoporosis
Meta-Analysis
Genes
Femur Neck
Risk Reduction Behavior
Spine
Alleles
Social Adjustment
Bone Fractures
Genetic Markers
Odds Ratio
Genotype
X-Rays
Research

ASJC Scopus subject areas

  • Medicine(all)

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Uitterlinden, A. G., Ralston, S. H., Brandi, M. L., Carey, A. H., Grinberg, D., Langdahl, B. L., ... Witteman, J. C. (2006). The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis. Annals of Internal Medicine, 145(4), 255-264.

The association between common vitamin D receptor gene variations and osteoporosis : A participant-level meta-analysis. / Uitterlinden, André G.; Ralston, Stuart H.; Brandi, Maria Luisa; Carey, Alisoun H.; Grinberg, Daniel; Langdahl, Bente L.; Lips, Paul; Lorenc, Roman; Obermayer-Pietsxch, Barbara; Reeve, Jonathan; Reid, David M.; Amedei, Antonietta; Bassiti, Amelia; Bustamante, Mariona; Husted, Lise Bjerre; Diez-Perez, Adolfo; Dobnig, Harald; Dunning, Alison M.; Enjuanes, Anna; Fahrleitner-Pammer, Astrid; Fang, Yue; Karczmarewicz, Elzbieta; Kruk, Marcin; Van Leeuwen, Johannes P T M; Mavilia, Carmelo; Van Meurs, Joyce B J; Mangion, Jon; McGuigan, Fiona E A; Pols, Huibert A P; Renner, Wilfried; Rivadeneira, Fernando; Van Schoor, Natasja M.; Scollen, Serena; Sherlock, Rachael E.; Ioannidis, John P A; Parsons, Claire; Bear, Stuart; Farmer, Rosie; Lukaszkiewicz, J.; Bilinski, P.; Czerwinski, E.; Lewinski, A.; Marcinowska-Suchowierska, E.; Milewicz, A.; Spaczynski, M.; Jaworski, M.; Nuti, R.; Grazio, S.; Miazgowski, T.; Boonen, R.; Masaryk, P.; Stepan, J. J.; Lopes Vaz, A.; Cannata, J.; Weber, K.; Benevolenskaya, L. I.; Todd, C.; Khaw, K. T.; Da Silva, J.; Bhalla, A.; Poór, G.; Bruges Armas, J.; Lyritis, G.; O'Neill, T. W.; Lunt, M.; Compston, Juliet; Cooper, Cyrus; Duncan, Emma; Keen, Richard; McLellan, Alastair; Wass, John; Dekema, Ebbo; Van Essen, Huub; Pluijm, Saskia; Bravenboer, Natalie; Hofman, Albert; Van Duijn, Cornelia M.; De Jong, Paulus J.; Breteler, Monique M.; Stricker, Bruno H.; Witteman, Jacqueline C.

In: Annals of Internal Medicine, Vol. 145, No. 4, 15.08.2006, p. 255-264.

Research output: Contribution to journalArticle

Uitterlinden, AG, Ralston, SH, Brandi, ML, Carey, AH, Grinberg, D, Langdahl, BL, Lips, P, Lorenc, R, Obermayer-Pietsxch, B, Reeve, J, Reid, DM, Amedei, A, Bassiti, A, Bustamante, M, Husted, LB, Diez-Perez, A, Dobnig, H, Dunning, AM, Enjuanes, A, Fahrleitner-Pammer, A, Fang, Y, Karczmarewicz, E, Kruk, M, Van Leeuwen, JPTM, Mavilia, C, Van Meurs, JBJ, Mangion, J, McGuigan, FEA, Pols, HAP, Renner, W, Rivadeneira, F, Van Schoor, NM, Scollen, S, Sherlock, RE, Ioannidis, JPA, Parsons, C, Bear, S, Farmer, R, Lukaszkiewicz, J, Bilinski, P, Czerwinski, E, Lewinski, A, Marcinowska-Suchowierska, E, Milewicz, A, Spaczynski, M, Jaworski, M, Nuti, R, Grazio, S, Miazgowski, T, Boonen, R, Masaryk, P, Stepan, JJ, Lopes Vaz, A, Cannata, J, Weber, K, Benevolenskaya, LI, Todd, C, Khaw, KT, Da Silva, J, Bhalla, A, Poór, G, Bruges Armas, J, Lyritis, G, O'Neill, TW, Lunt, M, Compston, J, Cooper, C, Duncan, E, Keen, R, McLellan, A, Wass, J, Dekema, E, Van Essen, H, Pluijm, S, Bravenboer, N, Hofman, A, Van Duijn, CM, De Jong, PJ, Breteler, MM, Stricker, BH & Witteman, JC 2006, 'The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis', Annals of Internal Medicine, vol. 145, no. 4, pp. 255-264.
Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL et al. The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis. Annals of Internal Medicine. 2006 Aug 15;145(4):255-264.
Uitterlinden, André G. ; Ralston, Stuart H. ; Brandi, Maria Luisa ; Carey, Alisoun H. ; Grinberg, Daniel ; Langdahl, Bente L. ; Lips, Paul ; Lorenc, Roman ; Obermayer-Pietsxch, Barbara ; Reeve, Jonathan ; Reid, David M. ; Amedei, Antonietta ; Bassiti, Amelia ; Bustamante, Mariona ; Husted, Lise Bjerre ; Diez-Perez, Adolfo ; Dobnig, Harald ; Dunning, Alison M. ; Enjuanes, Anna ; Fahrleitner-Pammer, Astrid ; Fang, Yue ; Karczmarewicz, Elzbieta ; Kruk, Marcin ; Van Leeuwen, Johannes P T M ; Mavilia, Carmelo ; Van Meurs, Joyce B J ; Mangion, Jon ; McGuigan, Fiona E A ; Pols, Huibert A P ; Renner, Wilfried ; Rivadeneira, Fernando ; Van Schoor, Natasja M. ; Scollen, Serena ; Sherlock, Rachael E. ; Ioannidis, John P A ; Parsons, Claire ; Bear, Stuart ; Farmer, Rosie ; Lukaszkiewicz, J. ; Bilinski, P. ; Czerwinski, E. ; Lewinski, A. ; Marcinowska-Suchowierska, E. ; Milewicz, A. ; Spaczynski, M. ; Jaworski, M. ; Nuti, R. ; Grazio, S. ; Miazgowski, T. ; Boonen, R. ; Masaryk, P. ; Stepan, J. J. ; Lopes Vaz, A. ; Cannata, J. ; Weber, K. ; Benevolenskaya, L. I. ; Todd, C. ; Khaw, K. T. ; Da Silva, J. ; Bhalla, A. ; Poór, G. ; Bruges Armas, J. ; Lyritis, G. ; O'Neill, T. W. ; Lunt, M. ; Compston, Juliet ; Cooper, Cyrus ; Duncan, Emma ; Keen, Richard ; McLellan, Alastair ; Wass, John ; Dekema, Ebbo ; Van Essen, Huub ; Pluijm, Saskia ; Bravenboer, Natalie ; Hofman, Albert ; Van Duijn, Cornelia M. ; De Jong, Paulus J. ; Breteler, Monique M. ; Stricker, Bruno H. ; Witteman, Jacqueline C. / The association between common vitamin D receptor gene variations and osteoporosis : A participant-level meta-analysis. In: Annals of Internal Medicine. 2006 ; Vol. 145, No. 4. pp. 255-264.
@article{ee84514019eb429a9e9df3c636238333,
title = "The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis",
abstract = "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.",
author = "Uitterlinden, {Andr{\'e} G.} and Ralston, {Stuart H.} and Brandi, {Maria Luisa} and Carey, {Alisoun H.} and Daniel Grinberg and Langdahl, {Bente L.} and Paul Lips and Roman Lorenc and Barbara Obermayer-Pietsxch and Jonathan Reeve and Reid, {David M.} and Antonietta Amedei and Amelia Bassiti and Mariona Bustamante and Husted, {Lise Bjerre} and Adolfo Diez-Perez and Harald Dobnig and Dunning, {Alison M.} and Anna Enjuanes and Astrid Fahrleitner-Pammer and Yue Fang and Elzbieta Karczmarewicz and Marcin Kruk and {Van Leeuwen}, {Johannes P T M} and Carmelo Mavilia and {Van Meurs}, {Joyce B J} and Jon Mangion and McGuigan, {Fiona E A} and Pols, {Huibert A P} and Wilfried Renner and Fernando Rivadeneira and {Van Schoor}, {Natasja M.} and Serena Scollen and Sherlock, {Rachael E.} and Ioannidis, {John P A} and Claire Parsons and Stuart Bear and Rosie Farmer and J. Lukaszkiewicz and P. Bilinski and E. Czerwinski and A. Lewinski and E. Marcinowska-Suchowierska and A. Milewicz and M. Spaczynski and M. Jaworski and R. Nuti and S. Grazio and T. Miazgowski and R. Boonen and P. Masaryk and Stepan, {J. J.} and {Lopes Vaz}, A. and J. Cannata and K. Weber and Benevolenskaya, {L. I.} and C. Todd and Khaw, {K. T.} and {Da Silva}, J. and A. Bhalla and G. Po{\'o}r and {Bruges Armas}, J. and G. Lyritis and O'Neill, {T. W.} and M. Lunt and Juliet Compston and Cyrus Cooper and Emma Duncan and Richard Keen and Alastair McLellan and John Wass and Ebbo Dekema and {Van Essen}, Huub and Saskia Pluijm and Natalie Bravenboer and Albert Hofman and {Van Duijn}, {Cornelia M.} and {De Jong}, {Paulus J.} and Breteler, {Monique M.} and Stricker, {Bruno H.} and Witteman, {Jacqueline C.}",
year = "2006",
month = "8",
day = "15",
language = "English",
volume = "145",
pages = "255--264",
journal = "Annals of Internal Medicine",
issn = "0003-4819",
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TY - JOUR

T1 - The association between common vitamin D receptor gene variations and osteoporosis

T2 - A participant-level meta-analysis

AU - Uitterlinden, André G.

AU - Ralston, Stuart H.

AU - Brandi, Maria Luisa

AU - Carey, Alisoun H.

AU - Grinberg, Daniel

AU - Langdahl, Bente L.

AU - Lips, Paul

AU - Lorenc, Roman

AU - Obermayer-Pietsxch, Barbara

AU - Reeve, Jonathan

AU - Reid, David M.

AU - Amedei, Antonietta

AU - Bassiti, Amelia

AU - Bustamante, Mariona

AU - Husted, Lise Bjerre

AU - Diez-Perez, Adolfo

AU - Dobnig, Harald

AU - Dunning, Alison M.

AU - Enjuanes, Anna

AU - Fahrleitner-Pammer, Astrid

AU - Fang, Yue

AU - Karczmarewicz, Elzbieta

AU - Kruk, Marcin

AU - Van Leeuwen, Johannes P T M

AU - Mavilia, Carmelo

AU - Van Meurs, Joyce B J

AU - Mangion, Jon

AU - McGuigan, Fiona E A

AU - Pols, Huibert A P

AU - Renner, Wilfried

AU - Rivadeneira, Fernando

AU - Van Schoor, Natasja M.

AU - Scollen, Serena

AU - Sherlock, Rachael E.

AU - Ioannidis, John P A

AU - Parsons, Claire

AU - Bear, Stuart

AU - Farmer, Rosie

AU - Lukaszkiewicz, J.

AU - Bilinski, P.

AU - Czerwinski, E.

AU - Lewinski, A.

AU - Marcinowska-Suchowierska, E.

AU - Milewicz, A.

AU - Spaczynski, M.

AU - Jaworski, M.

AU - Nuti, R.

AU - Grazio, S.

AU - Miazgowski, T.

AU - Boonen, R.

AU - Masaryk, P.

AU - Stepan, J. J.

AU - Lopes Vaz, A.

AU - Cannata, J.

AU - Weber, K.

AU - Benevolenskaya, L. I.

AU - Todd, C.

AU - Khaw, K. T.

AU - Da Silva, J.

AU - Bhalla, A.

AU - Poór, G.

AU - Bruges Armas, J.

AU - Lyritis, G.

AU - O'Neill, T. W.

AU - Lunt, M.

AU - Compston, Juliet

AU - Cooper, Cyrus

AU - Duncan, Emma

AU - Keen, Richard

AU - McLellan, Alastair

AU - Wass, John

AU - Dekema, Ebbo

AU - Van Essen, Huub

AU - Pluijm, Saskia

AU - Bravenboer, Natalie

AU - Hofman, Albert

AU - Van Duijn, Cornelia M.

AU - De Jong, Paulus J.

AU - Breteler, Monique M.

AU - Stricker, Bruno H.

AU - Witteman, Jacqueline C.

PY - 2006/8/15

Y1 - 2006/8/15

N2 - 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.

AB - 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.

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