RUNX2 T-1025C variant is associated with bone-related biochemical parameters and fracture risk in Maltese postmenopausal women

Abstract

BACKGROUND & OBJECTIVES: Runt-related transcription factor 2 (RUNX2) is a major transcription factor involved in osteoblast and chondrocyte differentiation, skeletogenesis and fracture repair. Transactivation of RUNX2 is under tight regulatory control particularly via promoter 2 (P2). The study aimed to assess the effect of the P2 RUNX2 T-1025C variant in relation to bone mineral density (BMD) at different anatomical sites, fracture risk and levels of biochemical parameters in the Maltese population.

METHODS: Genotyping was performed in 1,045 Maltese postmenopausal women from the Malta Osteoporotic Fracture Study using the TaqMan® fluoregenic 5' nuclease allelic discrimination assay. Genotype-phenotype associations were analysed using the Mann-Whitney statistic whereas odds ratios with 95% confidence intervals were computed using logistic regression analysis adjusted for confounders.

RESULTS: Genotyping was successful in 1,043 samples, with the reference T and alternative C alleles observed at a frequency of 0.92 and 0.08 respectively. Women aged >60 years with the TC genotype had higher total serum calcium (p=0.029) and lower total serum alkaline phosphatase (ALP) levels (p=0.046) relative to women with the TT genotype. Additionally, carriers of the C allele showed higher femoral neck BMD than homozygous carriers of the T allele. Nonetheless, the latter did not reach statistical significance (p>0.05). Homozygosity for the C allele was associated with an almost 5-fold increased fracture risk compared to homozygosity for the T allele, which was not attenuated after adjusting for BMD (adjusted OR: 4.9 [1.2-19.6], p=0.025). This is the first study to report an association with fractures. No association was seen with lumbar spine or total hip BMD.

CONCLUSION: Results indicate that the RUNX2 T-1025C is a possible genetic determinant of fracture risk in the Maltese population, as well as calcium and ALP control. This functional variant alters the binding of several transcriptional activators and repressors, possibly affecting bone composition and strength.