Background: Osteoporosis is a multifactorial skeletal disease characterised by low bone mass leading to increased fracture risk. Members of the low-density lipoprotein receptor-related protein (LRP) gene family play a role in osteoblastogenesis through the Wingless (Wnt)/βeta-catenin pathway. LRP4 controls the actions of sclerostin, a Wnt inhibitor, whereas LRP5 promotes bone formation. The aim was to evaluate the effect of four non-synonymous coding polymorphisms in relation to bone mineral density (BMD) and low-trauma fractures in Maltese postmenopausal women. Genotyped variants were the LRP4 rs2306033 (C>T) and rs6485702 (G>A) variants, and the LRP5 rs4988321 (G>A) and rs3736228 (C>T) variants.
Methods: Research subjects were 1045 women aged 40 to 79 years, subdivided in three BMD groups without a fracture history: normal, osteopenic or osteoporotic. Women with a fracture history were classified as cases. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism, or by real-time PCR. Odds ratios were computed using logistic regression analysis adjusted for age and clinical risk factors.
Results: Homozygosity for the rs6485702 G allele was found associated with low BMD at the lumbar spine, LS (P=0.01) relative to research subjects with a normal BMD, whereas heterozygotes for this allele had a low BMD at the femoral neck, FN (P=0.04). Women carrying one or two copies of the rs3736228 T allele and one copy of the rs4988321 A allele had a lower BMD at the LS and FN (P<0.05). The rs6485702 and rs3736228 variants were associated with increased fracture risk, however this was not independent of BMD. Interactions were observed between these three variants at the LS (P<0.01). Women carrying the LRP4 C-G haplotype and LRP5 A-T haplotype had lower BMD measurements at the LS and FN (P<0.05).
Conclusion: The LRP4 rs6485702 variant and the two LRP5 variants play a role in BMD regulation in Maltese postmenopausal women.
Disclosure: The authors declared no competing interests.