A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality
Val Mann, … , Richard M. Aspden, Stuart H. Ralston
Val Mann, … , Richard M. Aspden, Stuart H. Ralston
Published April 1, 2001
Citation Information: J Clin Invest. 2001;107(7):899-907. https://doi.org/10.1172/JCI10347.
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Article

A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality

Abstract

Osteoporosis is a common disease with a strong genetic component. We previously described a polymorphic Sp1 binding site in the COL1A1 gene that has been associated with osteoporosis in several populations. Here we explore the molecular mechanisms underlying this association. A meta-analysis showed significant associations between COL1A1 “s” alleles and bone mineral density (BMD), body mass index (BMI), and osteoporotic fractures. The association with fracture was stronger than expected on the basis of the observed differences in BMD and BMI, suggesting an additional effect on bone strength. Gel shift assays showed increased binding affinity of the “s” allele for Sp1 protein, and primary RNA transcripts derived from the “s” allele were approximately three times more abundant than “S” allele–derived transcripts in “Ss” heterozygotes. Collagen produced from osteoblasts cultured from “Ss” heterozygotes had an increased ratio of α1(I) protein relative to α2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2. Finally, the yield strength of bone derived from “Ss” individuals was reduced when compared with bone derived from “SS” subjects. We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality.

Authors

Val Mann, Emma E. Hobson, Baohua Li, Tracy L. Stewart, Struan F.A. Grant, Simon P. Robins, Richard M. Aspden, Stuart H. Ralston

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Meta-analysis of COL1A1 polymorphisms in relation to BMD and osteoporoti...
Meta-analysis of COL1A1 polymorphisms in relation to BMD and osteoporotic fractures. (a) Standardized mean difference (SMD) and 95% confidence intervals between the “SS” and “Ss” genotype groups for lumbar spine bone density (LS BMD). (b) Corresponding data for the “SS” versus “ss” genotype comparison. Also shown are the number of individuals studied, the mean and SD BMD values in each genotype group, and the weight and confidence intervals for individual studies. The results of heterogeneity testing and tests for overall effect are shown at the bottom left of each panel. Note that data from both populations studied by Grant et al. (3) are shown separately as Grant 1996a and Grant 1996b. (c) Odds ratios for fracture for the “SS” versus “Ss” genotype comparison. (d) Corresponding data for the “SS” versus “ss” comparison. Numbers in the cases and controls columns refer to the number of individuals with the risk genotype (“Ss” or “ss”) in relation to the total number of individuals studied. In the study of Uitterlinden et al. (8), data on both vertebral and nonvertebral fractures were available, and these are shown respectively as Uitterlinden 1998a and Uitterlinden 1998b.