Association of Functionally Different RUNX2 P2 Promoter Alleles With BMD

In these 264 subjects, we identified 16 allelic variations within the RUNX2 gene and promoters through DNA sequencing and denaturing high-performance liquid chromatography

James D Doecke


Scholarcy highlights

  • Specific osteoblast genes are induced by Runx2, a cell-specific transcription factor that is a candidate gene for controlling BMD
  • We previously identified a relationship between a synonymous coding polymorphism in exon 2 of RUNX2 and BMD in Geelong Osteoporosis Study, a random sample of Australian women. The magnitude of effect was an ∼0.35 SD increase in BMD at the femoral neck associated with the rare allele
  • A similar effect was observed in a study of females from Aberdeen. In addition, in the GOS, the genetic effect was more apparent in postmenopausal women. Despite the enhanced genetic effect in postmenopausal women, we ignored menopausal status and ranked all individuals from GOS according to age- and weight-adjusted femoral neck BMD and selected the upper and lower deciles to represent the extremes of the BMD distribution
  • We found a significant over-representation of the high BMD-related allele of single nucleotide polymorphism G>A+198 bp in the upper decile of femoral neck BMD, as expected according to the prior association with BMD and fracture. These data indicated that sampling the upper and lower deciles would be a reasonable strategy for identifying functional polymorphic markers that may explain the prior association with BMD
  • Other markers identified in RUNX2 showed varying degrees of linkage disequilibrium with the SNP G>A+198 bp, but the only markers that remained as candidates for a BMD association were those in the P2 promoter
  • If increased P2 promoter activity derived from polymorphisms is associated with higher BMD in humans, we might expect the magnitude of this genetic effect to vary across the skeleton, as we reported previously. The DNA binding species that interacts with the sequence of SNP T>C−1025 bp is a candidate for regulating the RUNX2 P2 promoter and influencing adult BMD

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