Polymorphisms in the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Gene Are Associated with Peak Bone Mass in Non-sedentary Men: Results from the Odense Androgen Study

Department of Endocrinology, Odense University Hospital, 5000, Odense C, Denmark.
Calcified Tissue International (Impact Factor: 3.27). 12/2007; 81(6):421-9. DOI: 10.1007/s00223-007-9088-z
Source: PubMed


To investigate the impact of the Ala1330Val (rs3736228, exon 18) and Val667Met (rs4988321, exon 9) polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene on peak bone mass in young men.
The Odense Androgen Study (OAS) is a population-based study comprising 783 Caucasian men aged 20-30 years. Genotyping was performed using real-time polymerase chain reaction (PCR) or fluorescence polarization. Bone mineral density (BMD) measurements were performed using dual-energy X-ray absorptiometry.
The CC, CT, and TT genotypes in Ala1330Val were found in 75.6%, 21.8%, and 2.6% of the participants, respectively. Similarly, the GG, GA, and AA genotypes of Val667Met were found in 89.7%, 9.8%, and 0.5%, respectively. For the Ala1330Val polymorphism, no significant differences between the genotypes were found regarding BMD in the overall study population. However, when analysis was restricted to non-sedentary men (n = 589), a significant association between the number of T-alleles and BMD in the spine and whole body were found. Each copy of the T-allele changed the Z-score of the spine by (median and 95% confidence interval) -0.21 [95% CI: -0.40; -0.03] (p < 0.02). Analysis suggested an association between the AA genotype in the Val667Met polymorphism and increased body height and decreased BMD of the femoral neck; however, no significant gene-dose effect of the A-allele could be demonstrated in the whole population. When the analysis was restricted to non-sedentary subjects, however, each number of A-alleles was associated with a change in Z-score of -0.26 [95% CI: -0.51; -0.01] (p = 0.04). No further significant results emerged with haplotype analysis.
The Ala1330Val and Val667Met polymorphisms in the LRP5 gene are significantly associated with peak bone mass in physically active men.

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Available from: Marianne Andersen
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    • "During the past two decades, it has become clear that many genes contribute to the variation in BMD in the general population; however, candidate gene association studies have led to conflicting and contradictory findings [25]. Nevertheless, there is clear evidence for the association between genetic variation of LRP5 and BMD in the general Caucasian and Chinese populations [18,19,21,26-30]. In African and North African populations, no information seems to be available about LRP5 and BMD variation. "
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    ABSTRACT: Background Osteoporosis is a highly heritable trait. Among the genes associated with bone mineral density (BMD), the low-density lipoprotein receptor-related protein 5 gene (LRP5) has been consistently identified in Caucasians. However LRP5 contribution to osteoporosis in populations of other ethnicities remains poorly known. Methods To determine whether LRP5 polymorphisms Ala1330Val and Val667Met are associated with BMD in North Africans, these genotypes were analyzed in 566 post-menopausal Tunisian women with mean age of 59.5 ± 7.7 years, of which 59.1% have low bone mass (T-score < −1 at spine or hip). Results In post-menopausal Tunisian women, 1330Val was weakly associated with reduced BMD T-score at lumbar spine (p = 0.047) but not femur neck. Moreover, the TT/TC genotypes tended to be more frequent in women with osteopenia and osteoporosis than in women with normal BMD (p = 0.066). Adjusting for body size and other potential confounders, LRP5 genotypes were no longer significantly associated with aBMD at any site. Conclusions The less common Val667Met polymorphism showed no association with osteoporosis. The Ala1330Val polymorphism is weakly associated with lower lumbar spine bone density and osteopenia/osteoporosis in postmenopausal Tunisian women. These observations expand our knowledge about the contribution of LRP5 genetic variation to osteoporosis risk in populations of diverse ethnic origin.
    Full-text · Article · Apr 2014 · BMC Musculoskeletal Disorders
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    • "For example, the AA genotype was 46%-73.5% in Asian women [23,25], however, much higher (73%) in Dutch women [22]. Among Caucasian populations, the AA genotype was detected in 56% of Dutch men [22], 91% of Finnish men [20], and 76% of Danish men [21]. In addition, there were statistically significant differences in A1330-allele frequencies with regard to gender in our study (P < 0.05). "
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    ABSTRACT: A number of studies have examined the association between the polymorphisms of the low-density lipoprotein receptor-related protein 5 gene (LRP5), but previous results have been inconclusive. Thus we performed a meta-analysis of studies on the association between the LRP5 polymorphisms and bone mineral density (BMD) to assess their pooled effects. Published literature from PubMed, EMBASE and ISI web of science were searched for eligible publications. Weighted mean difference (WMD) and 95% confidence interval (CI) was calculated using fixed- or random-effects model. A total of 19 studies with 25773 subjects were considered in this meta-analysis. Of them, 17 examined the association between the A1330V polymorphism and BMD, 8 were focused on the V667M polymorphism, and 2 analyzed the Q89R polymorphism. Individuals with the A1330V AA genotype showed significantly higher BMD than those with the AV/VV genotypes [at lumbar spine (LS): WMD = 0.02g/cm(2), 95% CI = 0.01-0.03, P < 10(-4); at femur neck (FN): WMD = 0.01g/cm(2), 95% CI = 0.00-0.02, P = 0.01] or VV genotype (at LS: WMD = 0.02g/cm(2), 95% CI = 0.01-0.04, P = 0.01). Significant associations were also detected in the analysis for V667M (VV vs. VM/MM: WMD at LS = 0.02g/cm(2), 95% CI = 0.02-0.03, P < 10(-5); WMD at FN = 0.01g/cm(2), 95% CI = 0.01-0.02, P = 0.0002). As for Q89R, subjects with the QQ genotype tended to have higher BMD than those with the QR/RR genotypes at FN (WMD = 0.03g/cm(2), 95% CI = 0.01-0.05, P = 0.005). This meta-analysis demonstrated that the LRP5 polymorphisms may be modestly associated with BMD of LS and FN.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "The three studies that were not included in this analysis found no significant association between the SNP rs3736228 (referred as SNP A1330V in the article) and BMD. Eventually, data from 10 studies [18,20,21,23,24,36-40] were included in the traditional analysis of association with BMD. In a recent large-scale analysis of the association between LRP5 polymorphisms and BMD or fracture in Caucasian individuals, the results were only shown effect sizes of the association [30]; therefore, this study was only able to be incorporated in the Bayesian approach. "
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    ABSTRACT: 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. 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. 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. 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.
    Full-text · Article · Feb 2008 · BMC Medical Genetics
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