Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 gene

Grant, Struan F A; Reid, David M.; Blake, Glen M.; Herd, R J; Fogelman, Ignac; Ralston, Stuart H.

doi:10.1038/ng1096-203

Cited by 583 publications

(440 citation statements)

References 26 publications

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“…Previous research identified associations between BMD and polymorphisms within the proximal promoter of COLIA1 (Garcia-Giralt et al 2002) and within the first intron of COLIA1 (Grant et al 1996). Most research has focused on a polymorphism within intron 1, which is situated at a binding site for the transcription factor Sp1.…”

Section: Collagen Type I␣ Imentioning

confidence: 99%

“…Classical association studies typically involve choosing a candidate gene that is known to have effects on bone metabolism on the basis of knowledge about skeletal physiology or bone biology. Genes that are mutated in rare monogenic bone diseases have also proved to be a rich source of polymorphisms that regulate BMD in the normal population (Grant et al 1996;Ferrari et al 2004;Sobacchi et al 2004;Pettersson et al 2005). Association studies are relatively easy to perform and can be powered to detect small effects, but spurious results are often reported due to confounding factors, small sample size, and population stratification (Ioannidis 2003).…”

Section: Association Studiesmentioning

confidence: 99%

“…Most research has focused on a polymorphism within intron 1, which is situated at a binding site for the transcription factor Sp1. The COLIA1 Sp1-binding site polymorphism has been associated with various osteoporosis-related phenotypes, including bone density (Grant et al 1996;Uitterlinden et al 1998), fragility fractures (Grant et al 1996;Uitterlinden et al 1998), postmenopausal bone loss (Harris et al 2000;MacDonald et al 2001), bone geometry (Qureshi et al 2001), bone quality (Mann et al 2001), and bone mineralization . Functional analysis has shown that the osteoporosis-associated T allele ("s") of the Sp1 polymorphism is associated with increased DNA-protein binding, increased transcription, and abnormally increased production of the COLIA1 mRNA and protein (Mann et al 2001).…”

Section: Collagen Type I␣ Imentioning

confidence: 99%

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Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

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289

228

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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Section: Collagen Type I␣ Imentioning

confidence: 99%

Section: Association Studiesmentioning

confidence: 99%

Section: Collagen Type I␣ Imentioning

confidence: 99%

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Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

Self Cite

289

228

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“…[13][14][15] Milder mutations in COL1A1 may also be associated with low BMD. 16,17 Linkage and association studies have suggested that some other genes that condition BMD are the vitamin D receptor (see 18 for review) and the estrogen receptor. 19 Linkage studies in two disorders, osteoporosis-pseudoglioma syndrome 20 and a high bone mass trait 21 indicate that a gene or genes on chromosome 11q can influence bone density.…”

Section: Introductionmentioning

confidence: 99%

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

Devoto

Shimoya

Caminis³

et al. 1998

Eur J Hum Genet

208

139

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Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. 1 In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was + 2.08 (θ = 0.05) for the marker CD3D on chromosome 11q. All other combined lod scores from the parametric analysis were less than + 1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Z max = + 3.51 for D1S450) and 2p23-24 (Z max = + 2.07 for D2S149). Maximum multi-point lod scores for these regions were + 2.29 and + 2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both singlepoint and multi-point non-parametric analysis was on chromosome 4qter (Z max = + 2.95 for D4S1539 and Z max = + 2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.

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“…It contains enhancers such as a CCAAT-box, Sp1-binding sites, and other GC-rich sequences (4,5). The first intron of the pro-␣1(I) collagen gene also contains positive regulatory elements such as an AP-1 binding site (6) or an Sp1-binding site that is involved in maintaining bone density (7). The role of this site in maintaining normal levels of expression of the pro-␣1(I) collagen gene throughout life has been shown by knock-in experiments (8).…”

mentioning

confidence: 99%

δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

Terraz¹,

Toman²,

Delauche³

et al. 2001

Journal of Biological Chemistry

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The transcription of type I collagen genes is tightly regulated, but few cis-acting elements have been identified that can modulate the levels of expression of these genes. Generation of transgenic mice harboring various segments of the mouse pro-␣1(I) collagen promoter led us to suspect that a repressor element was located between ؊10.5 and ؊17 kilobase pairs. Stable and transient transfection experiments in ROS17/2.8 osteoblastic cells confirmed the existence of such a repressor element at about ؊14 kilobase pairs and showed that it consisted in an almost perfect three-time repeat of a 41-base pair sequence. This element, which we named COIN-1, contains three E2-boxes, and a point mutation in at least two of them completely abolished its repressor effect. In gel shift assays, COIN-1 bound a DNAbinding protein named ␦EF1/ZEB-1, and mutations that abolished the repressor effect of COIN-1 also suppressed the binding of ␦EF1. We also showed that the repressor effect of COIN-1 was not mediated by chromatin compaction. Furthermore, overexpression of ␦EF1 in ROS17/ 2.8 osteoblastic cells enhanced the inhibitory effect of COIN-1 in a dose-dependent manner and repressed the expression of the pro-␣1(I) collagen gene. Thus, ␦EF1 appears to repress the expression of the mouse pro-␣1(I) collagen gene, through its binding to COIN-1.Type I collagen is a fibrillar collagen composed of two ␣1 chains and one ␣2 chain coiled around each others in a triple helix. It is the most abundant protein of mammalian bodies, and a major component of most extracellular matrices. In the extracellular space, type I collagen molecules self-assemble into highly organized fibrils and then fibers, which largely contribute to the high tensile strength of the structural framework supporting body structures (reviewed in Ref.

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Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 gene

Cited by 583 publications

References 26 publications

Genetic regulation of bone mass and susceptibility to osteoporosis

Genetic regulation of bone mass and susceptibility to osteoporosis

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

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