Low density lipoprotein receptor-related protein 5 gene polymorphisms and osteoporosis in Thai menopausal women

Abstract

Background: Osteoporosis, characterized by low bone mineral density (BMD) and high bone fracture risk, is prevalent in Thai menopausal women. Genetic factors are known to play a key role in BMD. Low density lipoprotein receptor-related protein 5 (LRP5), a co-receptor in the Wnt/beta-catenin pathway, is involved in many aspects of bone biology. As coding single nucleotide polymorphisms (cSNPs) of LRP5, including A1330V (rs3736228), and Asian-related Q89R (rs41494349) and N740N (rs2306862), are associated with lowered BMD, this study aimed to determine the relationship between these LRP5 polymorphisms and BMD in 277 Thai menopausal women.

Results: Only rs3736228 deviated from the Hardy-Weinberg equilibrium of allele frequency (p = 0.022). The median, range and p value for the BMD related to each SNP parameter were compared (Mann-Whitney U test). Significant differences were observed between wild-type and risk alleles for both rs3736228 (total radial, p = 0.011; and radial 33, p = 0.001) and rs2306862 (radial 33: p = 0.015) SNPs, with no significant difference for rs41494349 SNP. Linkage disequilibrium was strong for both rs3736228 and rs2306862 SNPs. Haplotype analysis identified high CC frequency in both normal and osteopenia/osteoporosis groups, with a significant odds ratio for carrying the TT haplotype; however, this was non-significant after adjusting for age. Multivariate binary logistic regression analysis performed for rs3736228 showed that individuals with a body mass index <25 kg/m(2) had an increased risk of osteoporosis for each decade, but the polymorphism had no effect.

Conclusions: This study did not identify LRP5 polymorphisms as a risk factor for osteoporosis in Thai menopausal women. Further studies with larger sample sizes are needed to further clarify the role of LRP5 as a genetic determinant of osteoporosis.

Keywords: Coding single nucleotide polymorphisms; Low density lipoprotein receptor-related protein 5 (LRP5); Menopausal Thai women; Osteopenia; Osteoporosis.

Fig. 1

Linkage disequilibrium plot between LRP5 SNPs showing region the rs3736228 and rs2306862 located using HapMap populations determined by Haploview 4.2 program. Each black triangle depicts haplotype blocks. LD is reported as D’. Bright red represents D’ = 1 and LOD ≥ 2, blue represents D’ = 1 and LOD < 2, pink represents D’ < 1, and LOD ≥ 2, and white represents D’ < 1 and LOD < 2. The r ² values are shown in blocks. The rs3736228 and rs2306862 are indicated by boxes. CHB, Han Chinese in Beijing, China; JPT, Japanese in Tokyo, Japan

Fig. 2

Fragment patterns of LRP5 SNPs with a 100 bp marker. M, Marker