Analysis of genetic polymorphisms in relation to bone mineral density and fracture risk in Maltese postmenopausal women

Abstract

BACKGROUND: Osteoporosis is a hereditary multifactorial disease characterised by low bone mass leading to an increased susceptibility to fracture. Bone mineral density (BMD) is the most widely used predictor of fracture risk. Gene variants have been found associated with a low BMD and increased fracture risk; nonetheless studies have identified the relationship between susceptibility genes and fractures independent of BMD.

OBJECTIVE: Eight single nucleotide polymorphisms (SNPs) within four candidate genes were investigated for their effect on BMD at different anatomical sites and with different low-trauma fractures.

METHODS: One thousand and forty-five maltese postmenopausal women were recruited and BMD measurements were performed by dual-energy X-ray absorptiometry. Women who suffered low-trauma fractures were classified as cases whereas subjects without a fracture history were included as controls. Informed consent was obtained from all participants. Genotyping was performed by PCR followed by restriction fragment length polymorphism, and RT PCR high resolution melt.

RESULTS: Using logistic regression analysis adjusted for age, three SNPs in three genes (LRP5 (rs3736228), RANK (rs3018362) and OPG (rs2073618)) were found associated with a low BMD and increased risk of all-type of low trauma fractures (P<0.05). SNPs rs3736228 and rs3018362 were associated with reduced BMD at the spine and femoral neck, whereas rs2073618 was only linked to low spine BMD. Three SNPs in the OPG gene (rs3134069, rs3102735 and rs2062377) were associated with an increased fracture risk that conversely did not affect BMD. The haplotype carrying the risk alleles for rs3736228, rs3018362, rs3134069, rs3102735 and rs2062377 was associated with increased fracture risk (permutated P-value = 0.01) as opposed to the haplotype reference which was strongly linked to a high BMD and low fracture risk (permutated P-value=0.0001).

CONCLUSION: Results from this independent replication study indicate that a number of gene variants are associated with reduced BMD and/or increased fracture susceptibility in Maltese postmenopausal women.