Bone Abstracts

Background: LRP4 gene encodes a member of the LDL receptor gene family, expressed by osteoblasts, which negatively regulates Wnt/β-catenin signalling by potentiating the inhibitory effect of sclerostin on LRP5 signalling. Previously, missense mutations of LRP4 have been described in patients with the phenotype of sclerosteosis, a disease associated with high bone mass and bone overgrowth. Here we investigated the hypothesis the LRP4 mutations might also be involved in regulating bone mass in general population.

Methods: We conducted mutation screening of LRP4 in subjects with bone mineral density (BMD) values above the 98th centile in the Orkney Complex Disease Study (ORCADES) cohort, a population isolated from the UK, and conducted an association study of LRP4 variants in relation to BMD in the whole study population of 1567 subjects (599 males and 968 females).

Results: We found a novel mutation in LRP4, 316+1G>A, and identified several known polymorphisms in LRP4 that cause amino acid substitutions (rs118009068, rs72897663, rs6485702, rs2306033, rs2306029 and rs3816614) and a silent change, rs61746928. Mutation 316+1G>A had an allele frequency of 0.0053 and showed an association with whole body BMD (P=0.045) in females. We also reported, for the first time, an association with rs2306033 (p.Ala1203Val) and spine BMD in females (wt=0.98±10.15; heterozygous=0.94±90.16; homozygous=0.955±0.18; P=0.042). Surprisingly, rs61746928 was strongly associated with spine BMD (P=0.004), and whole body BMD (P=0.05) in males after correcting for age, BMI, smoking, alcohol and calcium intake. The effect size in the seven heterozygous carriers of the p.Arg1273Arg allele was large, amounting to approximately 0.163 g/cm² or 0.673 T-score units.

Conclusions: We have confirmed that LRP4 is a candidate gene for regulating BMD and have identified a silent variant with large effect size that is associated with increased spine BMD in males, although further functional analysis should be performed to address its role in regulating BMD.