rs312009

This functional study demonstrates that rs312009, a bone mineral density-associated SNP in the LRP5 5' region, modulates LRP5 promoter activity in an allele-specific manner through RUNX2 transcription factor binding. The T allele shows stronger transcriptional activity than the C allele, and RUNX2 inhibition by RNAi reduces endogenous LRP5 mRNA by ~60% in U-2 OS cells. Five RUNX2 binding sites were identified and characterized in the LRP5 upstream region, revealing direct RUNX2 regulation of LRP5 for the first time.

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 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.