Tanya Vaughan

Griffith University, Southport, Queensland, Australia

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Publications (12)33.53 Total impact

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    ABSTRACT: Osteoporosis is a complex multi-factorial disease where environment, diet and genetics play a role in determining susceptibility. Patients with existing vertebral fracture have a heightened risk of further recurrent vertebral fracture. The efficacy of new osteoporosis therapies is often compared to calcium supplementation. 1,25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) and is effective at reducing recurrent vertebral fracture risk. Because the VDR controls calcium metabolism, we hypothesized that genetic variation at the VDR locus may influence response to both calcium and calcitriol therapy. Postmenopausal women with osteoporosis from a 3-year study comparing calcitriol versus calcium for prevention of vertebral fractures were genotyped for VDR alleles detected by FokI, BsmI, ApaI and TaqI. Data were analysed by hierarchical log-linear analysis and robust analysis of variance for relationships to fracture outcomes. Significant differences in the vertebral fracture rate in response to calcium therapy were observed between VDR genotypes (P<0.001). Calcium appeared to be equally effective as calcitriol in particular genotypes. The response to calcitriol therapy was most pronounced in patients carrying the TaqI t allele in combination with the FokI f initiation codon variant: f+t+ carriers were 11.3-fold less likely to sustain recurrent vertebral fracture in the last 2 years of the trial while on calcitriol therapy compared to calcium (P=1.4x10(-5)). Response to both calcium and calcitriol therapy is dependent on genetic variation at the VDR locus and two loci in the VDR gene may contribute to this effect.
    Pharmacogenetics and Genomics 02/2005; 15(2):127-35. · 3.61 Impact Factor
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    ABSTRACT: Differential expression of TBP-2 and Trx-1 occurs during osteoclastogenesis. Adenoviral overexpression of TBP-2 in osteoclast precursors inhibits Trx-1 expression, osteoclast formation, and AP-1 binding activity. TBP-2 and Trx-1 are key regulators of osteoclastogenesis. Thioredoxin binding protein-2 (TBP-2) negatively regulates thioredoxin-1 (Trx-1), a key endogenous modulator of cellular redox and signaling. In gene array analysis, we found that TBP-2 expression was reduced during human osteoclast differentiation compared with macrophage differentiation. Our aim was to determine the roles of TBP-2 and Trx-1 in human osteoclastogenesis and RANKL signaling. Osteoclasts or macrophages were generated from colony-forming unit-granulocyte macrophage (CFU-GM) precursors treated with sRANKL and macrophage-colony-stimulating factor (M-CSF), or M-CSF alone, respectively. Expression of TBP-2 and Trx-1 was quantified by real-time PCR and Western analysis. Adenoviral gene transfer was used to overexpress TBP-2 in precursors. NF-kappaB and activator protein 1 (AP-1) signaling was assessed with EMSA. In the presence of sRANKL, expression of TBP-2 was decreased, whereas Trx-1 expression was increased. The antioxidant N-acetylcysteine reversed this pattern and markedly inhibited osteoclastogenesis. Adenoviral overexpression of human TBP-2 in precursors inhibited osteoclastogenesis and Trx-1 expression, inhibited sRANKL-induced DNA binding of AP-1, but enhanced sRANKL-induced DNA binding of NF-kappaB. These data support significant roles for TBP-2 and the Trx system in osteoclast differentiation that are mediated by redox regulation of AP-1 transcription. A likely mechanism of stress signal induction of bone resorption is provided. Modulators of the Trx system such as antioxidants have potential as antiresorptive therapies.
    Journal of Bone and Mineral Research 12/2004; 19(12):2057-64. · 6.13 Impact Factor
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    ABSTRACT: Bone mineral density (BMD) is influenced by both environmental and genetic factors. We previously reported the association of the RUNX2 A allele with increased bone mineral density (BMD) and protection against a common form of osteoporotic fracture within a Geelong population. We genotyped 991 women from a Scottish cohort to decipher the role of RUNX2 alleles in regulating BMD. The alleles of RUNX2 within the glutamine-alanine repeat were determined by MspA1I restriction digest. Allele frequencies estimated from Scottish cohort were G allele, 0.87 +/- 0.01; A allele, 0.08 +/- 0.01; and 11Ala alanine deletion allele, 0.05 +/- 0.01. Analysis of covariance (ANCOVA) was used to adjust for the covariates weight and age for BMD at the femoral neck (FN). The A allele was associated with higher FN BMD (P = 0.035) within a postmenopausal subgroup of the population (n = 312). The effect of RUNX2 A alleles increased with increasing weight; A alleles were associated with FN BMD in those above the median BMI (BMI > 25), while no association was observed in thin/normal (BMI </= 25) postmenopausal women. Glutamine variants and an alanine insertion were identified within the group. These data suggest that the RUNX2 alleles are associated with BMD in a menopause- and weight-dependent manner.
    Bone 06/2004; 34(6):1029-36. · 3.82 Impact Factor
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    ABSTRACT: We previously reported the association of the RUNX2 A allele with increased bone mineral density (BMD) and protection against a common form of osteoporotic fracture within a Geelong population. To further decipher the role of the RUNX2 A allele we genotyped 992 women from a Scottish cohort. The A allele was associated with higher femoral neck (FN) BMD (p=0.035) within a postmenopausal subgroup of the population (n=312). When the postmenopausal group was segregated into thin/normal (BMI ≤ 25 kg/m2) and overweight /obese (BMI > 25 kg/m2), within the BMI > 25 kg/m2 group (n=140) the RUNX2 A allele showed a stronger effect on FN BMD, with the A allele accounting for 6.8% of the variance of FN BMD. Significant differences in FN BMD were detected in both A allele carriers (GA and AA genotypes) and non-A allele carriers (GG genotype) when comparing thin/normal women to overweight/obese women. The 11Ala RUNX2 deletion allele was significantly associated with decreased lumbar spine (LS) BMD (p=0.018) within the BMI > 25 kg/m2 group (n=546) of the whole group. The 11Ala allele was significantly associated with increased levels of pyridinoline (p=0.014) and deoxypyridinoline (p=0.038) in the HRT treated subgroup of the population (n=492). Glutamine variants and an alanine insertion were identified within the group. These data suggest that the RUNX2 11Ala and A alleles exert differing affects on BMD showing preference for different skeletal sites. No Yes
    01/2003;
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    ABSTRACT: Using gene array analysis, we found that thioredoxin (TRX) binding protein-2 (TBP-2) was down-regulated during osteoclast (OC) differentiation. TBP-2 is a negative regulator of TRX, a small protein with a redox-active dithiol active site. TRX enhances DNA binding of redox-sensitve transcription factors such as NFºB and AP-1. OC were generated on dentine slices using human CFU-GM precursor cells treated with RANKL and M-CSF. At 4 days of culture, efficient (>80%) infection with adenovirus expressing ²-galactosidase (AdLacZ) was achieved. Infection with adenovirus expressing TBP-2 (AdTBP-2) for 14 days resulted in 66% reduction in the total TRAP+ area and 50% reduction in OC numbers as compared to the AdLacZ control. The size of OC formed in the presence of AdTBP-2 was reduced by 66% and they contained fewer nuclei. Resorption of dentine was inhibited by 80%. In mature OC infected with AdTBP-2, RANKL-induced NFºB activation was reduced by 63% and Western analysis demonstrated markedly increased expression of TBP-2 protein. We have shown that the over-expression of TBP-2, a gene down-regulated during OC formation, inhibits OC differentiation and NFºB activation. These results are consistent with the known function of TBP-2 as a negative regulator of TRX and the importance of the redox-sensitive transcription factor NFºB in osteoclastogenesis. No Yes
    01/2003;
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    ABSTRACT: The aim of this study was to determine if DNA polymorphism within runt-related gene 2 (RUNX2)/core binding factor A1 (CBFA1) is related to bone mineral density (BMD). RUNX2 contains a glutamine-alanine repeat where mutations causing cleidocranial dysplasia (CCD) have been observed. Two common variants were detected within the alanine repeat: an 18-bp deletion and a synonymous alanine codon polymorphism with alleles GCA and GCG (noted as A and G alleles, respectively). In addition, rare mutations that may be related to low BMD were observed within the glutamine repeat. In 495 randomly selected women of the Geelong Osteoporosis Study (GOS), the A allele was associated with higher BMD at all sites tested. The effect was maximal at the ultradistal (UD) radius (p = 0.001). In a separate fracture study, the A allele was significantly protective against Colles' fracture in elderly women but not spine and hip fracture. The A allele was associated with increased BMD and was protective against a common form of osteoporotic fracture, suggesting that RUNX2 variants may be related to genetic effects on BMD and osteoporosis.
    Journal of Bone and Mineral Research 09/2002; 17(8):1527-34. · 6.13 Impact Factor
  • Bone 01/2000; 27(4):16-16. · 3.82 Impact Factor
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    ABSTRACT: Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.
    International Journal of Cancer 01/2000; 83(6):723-6. · 6.20 Impact Factor
  • Bone 01/2000; 27(4):19-19. · 3.82 Impact Factor
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