Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes

the GENOMOS study

Stuart H Ralston, Andre G Uitterlinden, Maria Luisa Brandi, Susana Balcells, Bente L Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsch, Serena Scollen, Mariona Bustamante, Lise Bjerre Husted, Alisoun H Carey, Adolfo Diez-Perez, Alison M. Dunning, Alberto Falchetti, Elzbieta Karczmarewicz, Marcin Kruk, Johannes P T M van Leeuwen, Joyce B J van Meurs, Jon Mangion & 12 others Fiona E A McGuigan, Leonardo Mellibovsky, Francesca del Monte, Huibert A P Pols, Jonathan Reeve, David M Reid, Wilfried Renner, Fernando Rivadeneira, Natasja M van Schoor, Rachael E Sherlock, John P A Ioannidis, GENOMOS Invest

Research output: Contribution to journalArticle

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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 COLIA1 alleles in relation to these phenotypes.
Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.
Conclusions Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

Original languageEnglish
Article numbere90
Number of pages9
JournalPLoS Medicine
Volume3
Issue number4
DOIs
Publication statusPublished - 21 Feb 2006

Keywords

  • bone-mineral density
  • vertebral deformity
  • binding site
  • in vitro
  • women
  • gene
  • men
  • association
  • population
  • fractures

Cite this

Ralston, S. H., Uitterlinden, A. G., Brandi, M. L., Balcells, S., Langdahl, B. L., Lips, P., ... GENOMOS Invest (2006). Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Medicine, 3(4), [e90]. https://doi.org/10.1371/journal.pmed.0030090

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes : the GENOMOS study. / Ralston, Stuart H; Uitterlinden, Andre G; Brandi, Maria Luisa; Balcells, Susana; Langdahl, Bente L; Lips, Paul; Lorenc, Roman; Obermayer-Pietsch, Barbara; Scollen, Serena; Bustamante, Mariona; Husted, Lise Bjerre; Carey, Alisoun H; Diez-Perez, Adolfo; Dunning, Alison M.; Falchetti, Alberto; Karczmarewicz, Elzbieta; Kruk, Marcin; van Leeuwen, Johannes P T M; van Meurs, Joyce B J; Mangion, Jon; McGuigan, Fiona E A; Mellibovsky, Leonardo; del Monte, Francesca; Pols, Huibert A P; Reeve, Jonathan; Reid, David M; Renner, Wilfried; Rivadeneira, Fernando; van Schoor, Natasja M; Sherlock, Rachael E; Ioannidis, John P A; GENOMOS Invest.

In: PLoS Medicine, Vol. 3, No. 4, e90, 21.02.2006.

Research output: Contribution to journalArticle

Ralston, SH, Uitterlinden, AG, Brandi, ML, Balcells, S, Langdahl, BL, Lips, P, Lorenc, R, Obermayer-Pietsch, B, Scollen, S, Bustamante, M, Husted, LB, Carey, AH, Diez-Perez, A, Dunning, AM, Falchetti, A, Karczmarewicz, E, Kruk, M, van Leeuwen, JPTM, van Meurs, JBJ, Mangion, J, McGuigan, FEA, Mellibovsky, L, del Monte, F, Pols, HAP, Reeve, J, Reid, DM, Renner, W, Rivadeneira, F, van Schoor, NM, Sherlock, RE, Ioannidis, JPA & GENOMOS Invest 2006, 'Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study', PLoS Medicine, vol. 3, no. 4, e90. https://doi.org/10.1371/journal.pmed.0030090
Ralston, Stuart H ; Uitterlinden, Andre G ; Brandi, Maria Luisa ; Balcells, Susana ; Langdahl, Bente L ; Lips, Paul ; Lorenc, Roman ; Obermayer-Pietsch, Barbara ; Scollen, Serena ; Bustamante, Mariona ; Husted, Lise Bjerre ; Carey, Alisoun H ; Diez-Perez, Adolfo ; Dunning, Alison M. ; Falchetti, Alberto ; Karczmarewicz, Elzbieta ; Kruk, Marcin ; van Leeuwen, Johannes P T M ; van Meurs, Joyce B J ; Mangion, Jon ; McGuigan, Fiona E A ; Mellibovsky, Leonardo ; del Monte, Francesca ; Pols, Huibert A P ; Reeve, Jonathan ; Reid, David M ; Renner, Wilfried ; Rivadeneira, Fernando ; van Schoor, Natasja M ; Sherlock, Rachael E ; Ioannidis, John P A ; GENOMOS Invest. / Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes : the GENOMOS study. In: PLoS Medicine. 2006 ; Vol. 3, No. 4.
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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 COLIA1 alleles in relation to these phenotypes. Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95{\%} confidence interval [CI]) BMD values were 25 mg/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Conclusions Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.",
keywords = "bone-mineral density, vertebral deformity, binding site, in vitro, women, gene, men, association, population, fractures",
author = "Ralston, {Stuart H} and Uitterlinden, {Andre G} and Brandi, {Maria Luisa} and Susana Balcells and Langdahl, {Bente L} and Paul Lips and Roman Lorenc and Barbara Obermayer-Pietsch and Serena Scollen and Mariona Bustamante and Husted, {Lise Bjerre} and Carey, {Alisoun H} and Adolfo Diez-Perez and Dunning, {Alison M.} and Alberto Falchetti and Elzbieta Karczmarewicz and Marcin Kruk and {van Leeuwen}, {Johannes P T M} and {van Meurs}, {Joyce B J} and Jon Mangion and McGuigan, {Fiona E A} and Leonardo Mellibovsky and {del Monte}, Francesca and Pols, {Huibert A P} and Jonathan Reeve and Reid, {David M} and Wilfried Renner and Fernando Rivadeneira and {van Schoor}, {Natasja M} and Sherlock, {Rachael E} and Ioannidis, {John P A} and {GENOMOS Invest}",
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T1 - Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes

T2 - the GENOMOS study

AU - Ralston, Stuart H

AU - Uitterlinden, Andre G

AU - Brandi, Maria Luisa

AU - Balcells, Susana

AU - Langdahl, Bente L

AU - Lips, Paul

AU - Lorenc, Roman

AU - Obermayer-Pietsch, Barbara

AU - Scollen, Serena

AU - Bustamante, Mariona

AU - Husted, Lise Bjerre

AU - Carey, Alisoun H

AU - Diez-Perez, Adolfo

AU - Dunning, Alison M.

AU - Falchetti, Alberto

AU - Karczmarewicz, Elzbieta

AU - Kruk, Marcin

AU - van Leeuwen, Johannes P T M

AU - van Meurs, Joyce B J

AU - Mangion, Jon

AU - McGuigan, Fiona E A

AU - Mellibovsky, Leonardo

AU - del Monte, Francesca

AU - Pols, Huibert A P

AU - Reeve, Jonathan

AU - Reid, David M

AU - Renner, Wilfried

AU - Rivadeneira, Fernando

AU - van Schoor, Natasja M

AU - Sherlock, Rachael E

AU - Ioannidis, John P A

AU - GENOMOS Invest

PY - 2006/2/21

Y1 - 2006/2/21

N2 - 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 COLIA1 alleles in relation to these phenotypes. Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Conclusions Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

AB - 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 COLIA1 alleles in relation to these phenotypes. Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm(2) (CI, 16 to 34 mg/cm(2)) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm(2) (CI, 1 to 42 mg/cm(2)), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Conclusions Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

KW - bone-mineral density

KW - vertebral deformity

KW - binding site

KW - in vitro

KW - women

KW - gene

KW - men

KW - association

KW - population

KW - fractures

U2 - 10.1371/journal.pmed.0030090

DO - 10.1371/journal.pmed.0030090

M3 - Article

VL - 3

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 4

M1 - e90

ER -