A common LRP4 haplotype is associated with bone mineral density and hip geometry in men-data from the Odense Androgen...

Osteoporosis is a common disease characterized by an increased susceptibility to fracture. It is a complex disorder resulting from the interaction of several polymorphisms in different genes and environmental factors. Since we recently reported a role for low density lipoprotein-related protein (LRP)-4 in monogenic disorders with bone overgrowth, we now wanted to evaluate whether genetic variation in the LRP4 gene has an effect on the susceptibility to osteoporosis in a population based cohort from the Odense Androgen Study. We chose to genotype four common (minor allele frequency (MAF)≥0.05) and non-synonymous coding polymorphisms located in the extracellular region of the LRP4 protein: rs3816614 (A/g), rs2306029 (G/a), rs2306033 (C/t) and rs6485702 (G/a) (large and small characters indicate major and minor alleles, respectively). Bone mineral density (BMD) measurements of the hip, the spine and whole body as well as different hip geometry parameters were available for a total of 1404 Danish men from two age groups ([20-29 years]: n=804; [60-74 years]: n=600). Using linear regression analysis adjusted for age, height and weight, we found significant associations between both rs2306029 and rs6485702 and BMD at all sites except the lumbar spine. The most significant association was found with whole body BMD (p=4.7×10(-5)). In addition, we found these two polymorphisms to be associated with different geometry parameters especially of the femoral shaft. Analysis of the two associated SNPs in the separate age groups demonstrated that most associations are only present in the youngest group of Danish men. In the group of elderly men, one Bonferroni corrected association between whole body BMD and rs6485702 was found to be significant. Subsequently, all polymorphisms were included in haplotype analyses using the PLINK software (v1.07). After adjusting for age, height and weight, two out of five common haplotypes (MAF≥0.01) were found to be of particular interest in the regulation of hip and whole body BMD (AGCG, AACA). Additional analysis suggested that these latter associations are driven by the association of rs6485702. We suggest, based on these results and the localisation of the variant in the third β-propeller domain of LRP4, that the variant has possibly a functional effect. Hereby, we conclude that common variation in the LRP4 gene determines hip and whole body BMD and thus confirm previous results from different GWAs. In addition, our data proves an additional role for LRP4 in regulating hip structure. Finally, interaction analysis for LRP4 with SOST and LRP5 showed interaction with LRP5 for femoral shaft geometry.