Analysis of the polyalanine repeat polymorphism in the RUNX2 gene in relation to bone mineral density and fracture risk in Maltese postmenopausal women

Abstract

INTRODUCTION: Runt-related transcription factor 2 (RUNX2) is a major transcription factor essential for the regulation of osteoblast and chondrocyte differentiation, hence affecting skeletogenesis, bone and cartilage formation. The RUNX2 protein has unique consecutive polyglutamine and polyalanine repeats (Q/A) which are important for its transactivation function. Several variants within the RUNX2 gene have been implicated in osteoporosis and fracture susceptibility.

AIM: To evaluate the association of an 18 bp deletion within the polyalanine tract (17A>11A; rs11498192) with bone mineral density (BMD) at lumbar spine (LS) and hip, and with different types of low-trauma fractures.

METHODS: A case-control collection of 1043 Maltese postmenopausal women was used. Women who suffered a fracture were classified as cases whereas those without a fracture history were included as controls. Genotyping was performed by polymerase chain reaction and odds ratios (OR) were computed using logistic regression analysis adjusted for confounders.

RESULTS: RUNX2 alleles were observed at a frequency of 0.90 and 0.10 for the 17A and 11A alleles, respectively, and which were found to be in Hardy-Weinberg equilibrium. Carriers of the 11A allele were found to have a twofold increased risk of osteoporosis at the total hip (adjusted OR: 2.1 [1.1–3.9], P=0.02) and to a lower extent at the femoral neck (adjusted OR: 1.7 [1.1–2.5], P=0.02). No association was observed for the LS BMD. Heterozygosity for the 11A allele was also associated with an increased hip fracture risk which was not attenuated after adjusting for BMD (adjusted OR: 2.2 [1.1–4.8], P=0.03).

CONCLUSION: Results from this independent replication study indicated that the RUNX2 11A variant predisposes to reduced BMD and increased fracture risk in a site-selective manner in Maltese postmenopausal women. The deletion is thought to alter the secondary structure of RUNX2 thereby affecting its transcriptional ability.