Association of the A1330V and V667M polymorphisms of LRP5 with bone mineral density in Greek peri- and postmenopausal women

Abstract

Wnt signaling through low-density lipoprotein receptor-related protein 5 (LRP5) is an important determinant of bone mass regulation. Objective To explore the influence of two LRP5 single nucleotide polymorphisms (SNPs) A1330V and V667M on bone mineral density (BMD) and serum levels of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) and bone metabolic markers in a Greek female population. Study design Two hundred and nine postmenopausal and twelve perimenopausal women aged 40–63 years were enrolled. All participants underwent spinal BMD evaluation. Genotyping of A1330V and V667M polymorphisms was performed by real-time polymerase chain reaction. Levels of OPG, soluble RANKL (sRANKL) and bone metabolic markers were measured. Results As regards A1330V SNP, women carrying CT/TT genotypes had lower spinal BMD than women with CC ( p < 0.0001). Regarding V667M SNP, spinal BMD was lower in women with GA/AA than in women with GG genotypes ( p < 0.0001). These differences remained significant after adjustment for age, years since menopause and body mass index. The A1330V and V667M polymorphisms were in strong linkage disequilibrium. A significant interaction between A1330V and V667M SNPs on spinal BMD was revealed. The haplotype with both risk alleles of the two SNPs (AT) conferred more risk for low BMD than the haplotypes with one risk allele (GT or AC) or the haplotype-reference (GC) ( p = 0.046, p = 0.045, and p = 0.010, respectively). No effect was observed on circulating OPG, sRANKL levels and bone metabolic markers. Conclusions These findings demonstrate that the A1330V and V667M polymorphisms are associated with low BMD in peri- and postmenopausal Greek women.