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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 alpha 1(I) protein relative to alpha 2(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.

SUBMITTER: Mann V

PROVIDER: S-EPMC199568 | biostudies-literature | 2001 Apr

REPOSITORIES: biostudies-literature

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

Mann V V Hobson E E EE Li B B Stewart T L TL Grant S F SF Robins S P SP Aspden R M RM Ralston S H SH

The Journal of clinical investigation 20010401 7

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 b ...[more]

PMID: 11285309

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Project description:Screening for osteoporosis with bone mineral density (BMD) is recommended for older adults. It is unclear whether repeating a BMD screening test improves fracture risk assessment.To determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification after a second BMD measure.Population-based cohort study involving 310 men and 492 women from the Framingham Osteoporosis Study with 2 measures of femoral neck BMD taken from 1987 through 1999.Risk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure.Mean age was 74.8 years. The mean (SD) BMD change was -0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio [HR], 1.43 [95% CI, 1.16 to 1.78]) and major osteoporotic fracture (HR, 1.21 [95% CI, 1.01 to 1.45]) after adjusting for baseline BMD. At 10 years' follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. In receiver operating characteristic (ROC) curve analyses, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance. The area under the curve (AUC) was 0.71 (95% CI, 0.65 to 0.78) for the baseline BMD model compared with 0.68 (95% CI, 0.62 to 0.75) for the BMD percent change model. Moreover, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance (AUC, 0.72 [95% CI, 0.66 to 0.79]). Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as high risk of hip fracture by 3.9% (95% CI, -2.2% to 9.9%), whereas it decreased the proportion classified as low risk by -2.2% (95% CI, -4.5% to 0.1%).In untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults this age untreated for osteoporosis.

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

Publications

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

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