Association analyses of 47,500 individuals identifies six fracture loci and 82 BMD loci clustering in biological pathways that regulate osteoblast and osteoclast activity

Estrada, Karol; Εvangelou, Εvangelos; Hsu, Yi Hsiang; Styrkársdóttir, Unnur; Liu, C T; Moayyeri, Alireza; Kaptoge, Stephen; Duncan, Emma L.; Amin, Najaf; Kiel, D.P.; Karasik, David; Brown, Melissa A.; Spector, Timothy D.; Zillikens, M. Carola; Ohlsson, Claes; Þorleifsson, Guðmar; Reeve, J.; Vandenput, Liesbeth; Pettersson, Ulrika; O'Neill, T.; Riancho, J A; Ijunggren, O; Rousseau, François; Leslie, William D.; Obermayer–Pietsch, Barbara; Alonso, Nerea; Langdahl, Bente; Nogués, Xavier; Prince, R.L.; Lips, Paul; Cheng, Saranette; Marc, Janja; Κollia, Panagoula; Brandi, M. L.; Hocking, Lynne J.; Khusnutdina, E; Cooper, Cyrus; Lehtimaki, Terho; Jackson, Rebecca D.; Koh, Jung‐Min; Minster, Ryan L.; Yerges-Armstrong, L.M.; Richards, Brent; Glazer, Nicole L.; Kung, Awc; Koller, Daniel L.; Evans, David M.; Ioannidis, J P A; Ralston, Stuart H.; Uitterlinden, André G.; Rivadeneira, Fernando; Consortia, Genomos

doi:10.1016/j.bone.2011.03.070

Cited by 7 publications

(6 citation statements)

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“…Indeed, our group, amongst others, has shown an association between some SNPs located at the SOST promoter and BMD [16]. On the other hand, a recent meta-analysis confirmed a relationship between SNPs located at the SOST and OSX promoters and BMD [17]. In this current work, we aimed to confirm whether OSX and RUNX2 bind to the SOST promoter and regulate SOST expression in humans.…”

Section: Introductionmentioning

confidence: 63%

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Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

et al. 2016

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Sclerostin, encoded by the SOST gene, works as an inhibitor of the Wnt pathway and therefore is an important regulator of bone homeostasis. Due to its potent action as an inhibitor of bone formation, blocking sclerostin activity is the purpose of recently developed anti-osteoporotic treatments. Two bone-specific transcription factors, RUNX2 and OSX, have been shown to interact and co-ordinately regulate the expression of bone-specific genes. Although it has been recently shown that sclerostin is targeted by OSX in mice, there is currently no information of whether this is also the case in human cells. We have identified SP-protein family and AML1 consensus binding sequences at the human SOST promoter and have shown that OSX, together with RUNX2, binds to a specific region close to the transcription start site. Furthermore, we show that OSX and RUNX2 activate SOST expression in a co-ordinated manner in vitro and that SOST expression levels show a significant positive correlation with OSX/RUNX2 expression levels in human bone. We also confirmed previous results showing an association of several SOST/RUNX2 polymorphisms with bone mineral density.

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Section: Introductionmentioning

confidence: 63%

“…We analysed the following SNPs: SOST, rs851056; RUNX2, rs2819854 and rs7771980; OSX, rs2016266. All have been associated with skeletal traits in previous studies [14,15,17,20]. They were analysed by using predesigned Taqman assays (Thermofisher Scientific), following manufacturer's instructions.…”

Section: Genetic Association Analysismentioning

confidence: 99%

Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

et al. 2016

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“…Osteoporotic fractures accounted for more Disability Adjusted Life Years (DALYs) lost than cancers, with the exception of lung cancer [4]. To advance understanding of the aetiology and pathogenesis of osteoporosis, there are now large-scale efforts to identify genes associated with fracture risk via genome-wide association studies (GWAS) of BMD [5][6][7][8]. The maintenance of BMD is not static, rather osteoblast and osteoclast differentiation processes are highly organized and driven by modifications in gene expression patterns throughout the life course [9].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and the social gradient of osteoporotic fracture: A conceptual model

Brennan-Olsen

Page

Berk

et al. 2016

Bone

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“…Wnt (β-catenin) binds to LRP receptor proteins (a low density lipoprotein-related protein) and FZDs (Frizzled receptors). Following the transfer of LRP and FZD into the nucleus of the pre-osteoblast and binding to transcription factor TCFS, proliferation and differentiation of this cell is induced (Whyte et al 2004, Glass et al 2005. Wnt inhibitors of canonical pathways, such as SFRP3 (encoded by the FRZB gene), DKK1-4 and sclerostin (encoded by the SOST gene) suppress bone formation.…”

Section: Rank-rankl-opg (Circuit Regulating Bone Remodeling)mentioning

confidence: 99%

Polymorphisms Associated With Low Bone Mass and High Risk of Atraumatic Fracture

Žofková

Nemcikova²,

Kuklik³

2015

Physiol Res

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Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In the pathogenesis of osteoporosis, except environment and internal factors, such as hormonal imbalance and genetic background, are also in play. In this study candidate genes for osteoporosis were classified according to metabolic or hormonal pathways, which regulate bone mineral density and bone quality (estrogen, RANKL/RANK/OPG axis, mevalonate, the canonical circuit and genes regulating the vitamin D system). COL1A1 and/or COL1A2 genes, which encode formation of the procollagen 1 molecule, were also studied. Mutations in these genes are well-known causes of the inborn disease ‘osteogenesis imperfecta’. In addition to this, polymorphisms in COL1A1 and/or COL1A2 have been found to be associated with parameters of bone quality in adult subjects. The authors discuss the perspectives for the practical utilization of pharmacogenetics (identification of single candidate genes using PCR) and pharmacogenomics (using genome wide association studies (GWAS) to choose optimal treatment for osteoporosis). Potential predictors of antiresorptive therapy efficacy include the following well established genes: ER, FDPS, Cyp19A1, VDR, Col1A1, and Col1A2, as well as the gene for the canonical (Wnt) pathway. Unfortunately, the positive outcomes seen in most association studies have not been confirmed by other researchers. The controversial results could be explained by the use of different methodological approaches in individual studies (different sample size, homogeneity of investigated groups, ethnic differences, or linkage disequilibrium between genes). The key pitfall of association studies is the low variability (7-10 %) of bone phenotypes associated with the investigated genes. Nevertheless, the identification of new genes and the verification of their association with bone density and/or quality (using both PCR and GWAS), remain a great challenge in the optimal prevention and treatment of osteoporosis.

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Association analyses of 47,500 individuals identifies six fracture loci and 82 BMD loci clustering in biological pathways that regulate osteoblast and osteoclast activity

Cited by 7 publications

References 0 publications

Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

DNA methylation and the social gradient of osteoporotic fracture: A conceptual model

Polymorphisms Associated With Low Bone Mass and High Risk of Atraumatic Fracture

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