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 MangionFiona 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

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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., Lorenc, R., Obermayer-Pietsch, B., Scollen, S., Bustamante, M., Husted, L. B., Carey, A. H., Diez-Perez, A., Dunning, A. M., Falchetti, A., Karczmarewicz, E., Kruk, M., van Leeuwen, J. P. T. M., van Meurs, J. B. J., ... 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