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

Ralston, Stuart H ; Uitterlinden, André G ; Brandi, Maria Luisa ; Balcells, Susana ; Langdahl, Bente L ; Lips, Paul ; Lorenc, Roman ; Obermayer-Pietsch, Barbara ; Scollen, Serena and Bustamante, Mariona , et al. (2006) In PLoS Medicine 3(4).
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... (More)

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/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (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.

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Adult, Aged, Aged, 80 and over, Bone Density, Case-Control Studies, Collagen Type I, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Osteoporosis, Polymorphism, Genetic, Risk Factors, Spinal Fractures, Multicenter Study
in
PLoS Medicine
volume
3
issue
4
article number
e90
publisher
Public Library of Science
external identifiers
  • pmid:16475872
  • scopus:33646248070
ISSN
1549-1676
DOI
10.1371/journal.pmed.0030090
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English
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9738a2f3-f40e-4158-80ee-f527e4ca993a
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2018-01-02 11:01:54
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2019-12-04 06:58:49
@article{9738a2f3-f40e-4158-80ee-f527e4ca993a,
  abstract     = {<p>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.</p><p>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/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p &lt; 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (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.</p><p>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.</p>},
  author       = {Ralston, Stuart H and Uitterlinden, André G and Brandi, Maria Luisa and Balcells, Susana and Langdahl, Bente L and Lips, Paul and Lorenc, Roman and Obermayer-Pietsch, Barbara and Scollen, Serena and Bustamante, Mariona and Husted, Lise Bjerre and Carey, Alisoun H and Diez-Perez, Adolfo and Dunning, Alison M and Falchetti, Alberto and Karczmarewicz, Elzbieta and Kruk, Marcin and van Leeuwen, Johannes P T M and van Meurs, Joyce B J and Mangion, Jon and McGuigan, Fiona E A and Mellibovsky, Leonardo and del Monte, Francesca and Pols, Huibert A P and Reeve, Jonathan and Reid, David M and Renner, Wilfried and Rivadeneira, Fernando and van Schoor, Natasja M and Sherlock, Rachael E and Ioannidis, John P A},
  issn         = {1549-1676},
  language     = {eng},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS Medicine},
  title        = {Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes : the GENOMOS study},
  url          = {http://dx.doi.org/10.1371/journal.pmed.0030090},
  doi          = {10.1371/journal.pmed.0030090},
  volume       = {3},
  year         = {2006},
}