Abstract
RUNX2 is a transcription factor essential for osteoblast differentiation and skeletal morphogenesis. Its mutation creates cleidocranial dysplasia (CCD), a disorder characterized by skeletal abnormalities and bone mineral density (BMD) alterations. The purpose of the present study has been to clarify whether polymorphisms affecting this gene could be associated with changes in BMD in women. To that end, we performed an association study of BMD values from 776 women with two single nucleotide polymorphisms (SNPs) located at P2 promoter (–1025 T>C) and at exon 2 (+198 G>A), and with a deletion polymorphism (17Ala>11Ala), also located at exon 2. We found an association of –1025 T>C SNP with femoral neck BMD (FN-BMD), being the women of TC/CC genotype who have higher BMD than women of TT genotype (P = 0.006). This association was independent of age, weight, menopausal status, or hormone replacement therapy (HRT) use as shown by regression analysis. When women of highest versus lowest quartile of BMD were compared, this association became more evident (P = 0.002), extending also to +198 G>A SNP (GA/AA women with higher FN-BMD; P < 0.05). In addition, we describe herein three novel rare variants in the polyglutamine domain of RUNX2 protein: an in-frame insertion and two deletions in exon 2, resulting in the insertions of 7 and deletions of 7 and 5 glutamines, respectively. These variants do not produce CCD, increased frequency of bone fracture, or BMD alterations. In conclusion, common polymorphisms in Runx2 are associated with FN-BMD. Nevertheless, rare variants that modify the polyglutamine domain of RUNX2 neither have any effect on BMD nor produce the CCD phenotype. These results underscore the significance of polymorphisms in the 5′-region of Runx2 in the determination of FN-BMD.
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Acknowledgments
The authors are indebted to Mrs. R. Aliaga and Mrs. E. Calap for their excellent technical assistance and to Dr. F.J. Chaves and Dr. S. Blesa for sequencing the rare variants. This work was supported by Grants PI06/154 from Fondo de Investigación Sanitaria (FIS, Madrid, Spain), AP-024/07, EVES 045-2007, and AP-077/08 from Conselleria de Sanitat (Generalitat Valenciana), Red HERACLES RD06/0009 from Instituto Carlos III (Ministerio de Ciencia e Innovación; Madrid, Spain), and Fundación Santiago Dexeus Font (Barcelona, Spain). MAG-P is a recipient of a research contract from Fondo de Investigación Sanitaria—Consellería de Sanitat (Generalitat Valenciana).
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Pineda, B., Hermenegildo, C., Laporta, P. et al. Common polymorphisms rather than rare genetic variants of the Runx2 gene are associated with femoral neck BMD in Spanish women. J Bone Miner Metab 28, 696–705 (2010). https://doi.org/10.1007/s00774-010-0183-2
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DOI: https://doi.org/10.1007/s00774-010-0183-2