rs3736228

A case-control study of 483 postmenopausal women examined associations between three SNPs (rs3736228 and rs4988321 in LRP5, rs1800795 in IL-6) and osteoporosis/osteopenia at multiple skeletal sites using dual-energy X-ray absorptiometry and real-time PCR genotyping. LRP5 polymorphisms were significantly associated with osteoporosis at the lumbar spine (rs3736228 p=0.018, rs4988321 p=0.032) and proximal femur (rs3736228 p=0.008, rs4988321 p=0.003), while IL-6 rs1800795 GG genotype was a risk factor for hip osteoporosis (p=0.045 for genotypes). The findings support LRP5 and IL-6 polymorphisms as contributing to postmenopausal osteoporosis development.

This Japanese cohort study of 206 elderly women (mean age 69.7 years) from the Obuse registry investigated associations between genetic variants and osteoarthritis (OA) prevalence. LRP5 rs3736228 showed significant associations with knee/hip OA (OR 7.28, 95% CI 2.22-28.08) and osteoporosis (OR 5.24, 95% CI 0.95-26.98). MTHFR rs1801133 showed a protective association with knee OA prevalence (OR 0.58, 95% CI 0.35-0.97). Other variants (LRP5 rs312009, GDF5 rs143383, SMAD3 rs12901499) showed no significant associations.

A population-based candidate gene study of 783 young Danish men examining associations between DKK1 polymorphisms and bone phenotypes. The study found no association between DKK1 variants and bone mineral density (BMD) or bone turnover markers, but identified a significant association between rs1569198 and hip axis length (HAL, P=0.012; P=0.004 in nonsedentary men), with each minor allele increasing HAL by 0.74-0.96 mm. The association with HAL was independent of BMD and height, suggesting a potential effect on hip fracture risk.

A nested case-control study of 309 postmenopausal osteoporotic women and 293 controls found that the IL6 -634G>C SNP (rs1800796) was associated with osteoporosis (OR 2.51, p=0.0047), independent of smoking or statin use. Additionally, the LRP5 C135242T SNP (rs545382) showed association with osteoporosis specifically in cigarette smokers (OR 2.8, p=0.03), suggesting a gene-environment interaction.

A replication study of 139 SNPs from three prior genome-wide association studies of bone mineral density in an independent sample of 1,000 unrelated US whites confirmed 38 SNPs (27% replication rate). Two SNPs achieved the most significant replication: rs3762397 in NR5A2 and rs3736228 in LRP5. Ten SNPs achieved combined p-values less than 3.6×10⁻⁴ across datasets, including rs3736228 (LRP5) with combined p=5.3×10⁻¹² for spinal BMD.

This study examined LRP5 polymorphisms in relation to bone mineral density (BMD) and response to risedronate treatment in 249 osteoporotic or osteopenic men over 24 months. The A1330V polymorphism was significantly associated with hip BMD at baseline, with Val/Val homozygotes having 8.4% higher total-hip BMD (P=0.009), 7.5% higher femoral neck BMD (P=0.015), and 11.7% higher trochanter BMD (P=0.002) compared to other genotype groups. However, no association was found between either LRP5 polymorphism (A1330V or V667M) and response to bisphosphonate treatment.

Large-scale GENOMOS consortium analysis of 37,534 individuals found that two common LRP5 variants (Val667Met: rs4988321 and Ala1330Val: rs3736228) are significantly associated with reduced bone mineral density and increased fracture risk. The Met667 allele was associated with 20 mg/cm² lower lumbar spine BMD (P=3.3×10⁻⁸) and OR 1.26 for vertebral fractures; Val1330 showed 14 mg/cm² lower lumbar spine BMD (P=2.6×10⁻⁹) and OR 1.12 for vertebral fractures. The LRP6 variant (Ile1062Val: rs2302685) was not associated with osteoporosis phenotypes.

This study investigated two polymorphisms in the LRP5 gene (Ala1330Val rs3736228 and Val667Met rs4988321) and their association with peak bone mass in 783 young Danish men. In non-sedentary (physically active) subjects, each copy of the T-allele at Ala1330Val was associated with a -0.21 Z-score change in lumbar spine BMD (p=0.02), and each A-allele at Val667Met showed a -0.26 Z-score change (p=0.04). The findings suggest a gene-environment interaction between LRP5 polymorphisms and physical activity in determining peak bone mass.

Mutation screening of 56 unrelated FEVR patients identified 10 novel mutations in LRP5 and FZD4 genes (detection rate 25%, 14/56). Nine missense or frameshift mutations were found in LRP5 including c.1330C>T [p.R444C] and compound heterozygous mutations, while two mutations were found in FZD4. Notably, a synergistic effect was observed in a family carrying both c.1330C>T [p.R444C] in LRP5 and c.1250G>A [p.R417Q] in FZD4. Reduced bone density was identified as a feature specific to LRP5 mutations.