Journal of Bone and Mineral Metabolism

, Volume 28, Issue 6, pp 696–705

Common polymorphisms rather than rare genetic variants of the Runx2 gene are associated with femoral neck BMD in Spanish women

  • Begoña Pineda
  • Carlos Hermenegildo
  • Paz Laporta
  • Juan J. Tarín
  • Antonio Cano
  • Miguel Ángel García-Pérez
Original Article

DOI: 10.1007/s00774-010-0183-2

Cite this article as:
Pineda, B., Hermenegildo, C., Laporta, P. et al. J Bone Miner Metab (2010) 28: 696. doi:10.1007/s00774-010-0183-2

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.

Keywords

OsteoporosisRunx2Bone mineral densityAssociationAlleles

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2010

Authors and Affiliations

  • Begoña Pineda
    • 1
  • Carlos Hermenegildo
    • 2
  • Paz Laporta
    • 3
  • Juan J. Tarín
    • 4
  • Antonio Cano
    • 5
  • Miguel Ángel García-Pérez
    • 1
  1. 1.Research FoundationHospital Clínico UniversitarioValenciaSpain
  2. 2.Department of PhysiologyUniversity of ValenciaValenciaSpain
  3. 3.Clinical Biochemistry ServiceHospital Clínico UniversitarioValenciaSpain
  4. 4.Department of Functional Biology and Physical AnthropologyUniversity of ValenciaValenciaSpain
  5. 5.Department of Pediatrics, Obstetrics and GynecologyUniversity of ValenciaValenciaSpain