Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

Abstract

Genetic determinants contribute to osteoporosis and enhance the risk of fracture. Genomewide association studies of unselected population-based individuals or families have identified polymorphisms in several genes related to low bone density, but not in osteoporotic patients with Z-score < -2.0 SD with fragility fracture(s). The aim of this study was to determine the causal genes of idiopathic osteoporosis in the adulthood. Also, we used next-generation sequencing of candidate genes in a cohort of 123 young or middle-aged adults with idiopathic osteoporosis. All patients were included if they had a low bone mineral density (Z-score < -2 SD), a diagnosis before age 55 years (mean ± SD, 48.4 ± 10.6 years; mean ± SD age at first fracture, 30.4 ± 17.4 years) and fracture or not. We found that 11 patients carried rare or novel variants in COL1A2 (n = 4), PLS3 (n = 2), WNT1 (n = 4), or DKK1 (n = 1). We showed a high prevalence of pathogenic variants in LRP5: 22 patients (17.8%) had the p.Val667Met variant, including three at the homozygous level and 16 (13%) carrying a novel or very rare variant. Functional analysis revealed that the LRP5 missense variants resulted in reduced luciferase activity, which indicates reduced activation of canonical WNT signaling. The clinical phenotype of patients carrying causal gene variants was indistinguishable. In conclusion, molecular screening of young osteoporotic adults revealed several variants and could be useful to characterize susceptibility genes for personalizing treatment, in particular for the new anabolic drugs.© 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Keywords: BONE; COLLAGEN; FRACTURE; LRP5; OSTEOPOROSIS; WNT.

Figure 1

Distribution of gene variants in young patients with idiopathic osteoporosis (n = 123). NGS sequencing was used to screen patients with idiopathic osteoporosis (Z‐score < −2 SD); 11 patients carried rare variants in COL1A2, PLS3, WNT1, and DKK1. Most patients carried LRP5 common and rare variants and 10 new variants were identified. HTZ = heterozygous; HMZ = homozygous.

Figure 2

LRP5 variants reduce activation of canonical Wnt signaling. Canonical Wnt signaling was induced by Wnt3a after WT or variant transfection in Saos2 cells. Wnt canonical pathway activity was analyzed by firefly luciferase activity and normalized to renilla luciferase activity. *p < 0.05, **p < 0.01 compared to WT. WT = wild‐type.