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The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood.

ABSTRACT: Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2,306,862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.

SUBMITTER: Koay MA

PROVIDER: S-EPMC2742716 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood.

Koay M Audrey MA Tobias Jonathan H JH Leary Sam D SD Steer Colin D CD Vilariño-Güell Carles C Brown Matthew A MA

Calcified tissue international 20070516 1

Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bon ...[more]

PMID: 17505772

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Project description:BACKGROUND: The low-density lipoprotein receptor-related protein 5 gene (LRP5) was identified to be linked to the variation in BMD in high bone mass pedigrees. Subsequent population-based studies of the association between the LRP5 gene and BMD have yielded conflicting results. The present study was aimed at examining the association between LRP5 gene and BMD by using meta-analysis. METHODS: A systematic electronic search of literature was conducted to identify all published studies in English on the association between LRP5 gene and osteoporosis-related phenotypes, including bone mineral density and fracture. BMD data were summarized from individual studies by LRP5 genotype, and a synthesis of data was performed with random-effects meta-analyses. After excluding studies on animal and review papers, there were 19 studies for the synthesis. Among these studies, 10 studies used the rs3736228 (A1330V) polymorphism and reported BMD values. RESULTS: The 10 eligible studies comprised 16,705 individuals, with the majority being women (n = 8444), aged between 18 - 81 years. The overall distribution of genotype frequencies was: AA, 68%, AV and VV, 32%. However, the genotype frequency varied significantly within as well as between ethnic populations. On random-effects meta-analysis, lumbar spine BMD among individuals with the AA genotype was on average 0.018 (95% confidence interval [CI]: 0.012 to 0.023) g/cm2 higher than those with either AV or VV genotype. Similarly, femoral neck BMD among carriers of the AA genotype was 0.011 (95%CI: 0.004 to 0.017) g/cm2 higher than those without the genotype. While there was no significant heterogeneity in the association between the A1330V polymorphism and lumbar spine BMD (p = 0.55), the association was heterogeneous for femoral neck BMD (p = 0.05). The probability that the difference is greater than one standard deviation was 0.34 for femoral neck BMD and 0.54 for lumbar spine BMD. CONCLUSION: These results suggest that there is a modest effect of the A1330V polymorphism on BMD in the general population, and that the modest association may limit its clinical use.

Project description:PurposeFamilial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models for Lrp5, Fzd4, and Ndp have proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant, tvrm111B, which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program.MethodsERGs were used to examine outer retinal physiology. The retinal vasculature was examined by in vivo retinal imaging, as well as by histology and immunohistochemistry. The tvrm111B locus was identified by genetic mapping of mice generated in a cross to DBA/2J, and subsequent sequencing analysis. Gene expression was examined by real-time PCR of retinal RNA. Bone mineral density (BMD) was examined by peripheral dual-energy X-ray absorptiometry.ResultsThe tvrm111B allele is inherited as an autosomal recessive trait. Genetic mapping of the decreased ERG b-wave phenotype of tvrm111B mice localized the mutation to a region on chromosome 19 that included Lrp5. Sequencing of Lrp5 identified the insertion of a cytosine (c.4724_4725insC), which is predicted to cause a frameshift that disrupts the last three of five conserved PPPSPxS motifs in the cytoplasmic domain of LRP5, culminating in a premature termination. In addition to a reduced ERG b-wave, Lrp5tvrm111B homozygotes have low BMD and abnormal features of the retinal vasculature that have been reported previously in Lrp5 mutant mice, including persistent hyaloid vessels, leakage on fluorescein angiography, and an absence of the deep retinal capillary bed.ConclusionsThe phenotype of the Lrp5tvrm111B mutant includes abnormalities of the retinal vasculature and of BMD. This model may be a useful resource to further our understanding of the biological role of LRP5 and to evaluate experimental therapies for FEVR or other conditions associated with LRP5 dysfunction.

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The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood.

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The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood.

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