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Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures.

ABSTRACT: Although many common variants have been identified for bone mineral density (BMD) and osteoporosis fractures, all the identified risk variants could only explain a small portion of heritability of BMD and osteoporosis fractures. OPG belongs to the tumor necrosis factor receptor superfamily, which plays a crucial role in bone remodeling and is thus a promising candidate gene of osteoporosis. Several studies have explored the association of OPG variants with BMD or osteoporosis fractures, however, the results remain inconsistent among different populations. In the study, we first assessed the relationship between OPG variants and BMD or osteoporosis fractures in our sample size (227 subjects with postmenopausal osteoporosis and 189 controls), and then performed a systematic meta-analysis. Among the nine SNPs genotyped, rs6469804 and rs2073618 showed significant associations with both BMD and osteoporotic fractures, while rs3102735 was only associated with BMD in our samples (P?

SUBMITTER: Sheng X

PROVIDER: S-EPMC5432005 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures.

Sheng Xiaoyong X Cai Guangyong G Gong Xingjun X Yao Zouying Z Zhu Ye Y

Scientific reports 20170511 1

Although many common variants have been identified for bone mineral density (BMD) and osteoporosis fractures, all the identified risk variants could only explain a small portion of heritability of BMD and osteoporosis fractures. OPG belongs to the tumor necrosis factor receptor superfamily, which plays a crucial role in bone remodeling and is thus a promising candidate gene of osteoporosis. Several studies have explored the association of OPG variants with BMD or osteoporosis fractures, however, ...[more]

PMID: 28496203

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Project description:BackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Project description:Osteoporosis, a disease characterized by low bone mineral density (BMD), increases the risk for fractures. Conventional risk factors alone do not completely explain measured BMD or osteoporotic fracture risk. Metabolomics may provide additional information. We aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 1552 Framingham Offspring Study participants, and measured femoral neck (FN) and lumbar spine (LS) BMD 2 to 10 years later using dual-energy X-ray absorptiometry. We assessed osteoporotic fractures up to 27-year follow-up after metabolomic profiling. We identified 27 metabolites associated with FN-BMD or LS-BMD by LASSO regression with internal validation. Incorporating selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors (area under the curve [AUC] = 0.74 for the model with identified metabolites and risk factors versus AUC = 0.70 with risk factors alone, p = .001; net reclassification index = 0.07, p = .03). We replicated significant improvement in fracture prediction by incorporating selected metabolites in 634 participants from the Hong Kong Osteoporosis Study (HKOS). The glycine, serine, and threonine metabolism pathway (including four identified metabolites: creatine, dimethylglycine, glycine, and serine) was significantly enriched (false discovery rate [FDR] p value = .028). Furthermore, three causally related metabolites (glycine, phosphatidylcholine [PC], and triacylglycerol [TAG]) were negatively associated with FN-BMD, whereas PC and TAG were negatively associated with LS-BMD through Mendelian randomization analysis. In summary, metabolites associated with BMD are helpful in osteoporotic fracture risk prediction. Potential causal mechanisms explaining the three metabolites on BMD are worthy of further experimental validation. Our findings may provide novel insights into the pathogenesis of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Project description:International variations in osteoporosis and fracture rates have been reported, with temporal trends differing between populations. We observed higher BMD and lower fracture prevalence in a recently recruited cohort compared to that of a cohort recruited 20 years ago, even after adjusting for multiple covariates.PurposeWe explored sex-specific differences in femoral neck bone mineral density (FN-BMD) and in prevalent major osteoporotic fractures (MOF) using two Canadian cohorts recruited 20 years apart.MethodsWe included men and women aged 50-85 years from the Canadian Multicentre Osteoporosis Study (CaMos, N = 6,479; 1995-1997) and the Canadian Longitudinal Study on Aging (CLSA, N = 19,534; 2012-2015). We created regression models to compare FN-BMD and fracture risk between cohorts, adjusting for important covariates. Among participants with prevalent MOF, we compared anti-osteoporosis medication use.ResultsMean (SD) age in CaMos (65.4 years [8.6]) was higher than in CLSA (63.8 years [9.1]). CaMos participants had lower mean body mass index and higher prevalence of smoking (p < 0.001). Adjusted linear regression models (estimates [95%CI]) demonstrated lower FN-BMD in CaMos women (- 0.017 g/cm2 [- 0.021; - 0.014]) and men (- 0.006 g/cm2 [- 0.011; 0.000]), while adjusted odds ratios (95%CI) for prevalent MOF were higher in CaMos women (1.99 [1.71; 2.30]) and men (2.33 [1.82; 3.00]) compared to CLSA. In women with prevalent MOF, menopausal hormone therapy use was similar in both cohorts (43.3% vs 37.9%, p = 0.076), but supplements (32.0% vs 48.3%, p < 0.001) and bisphosphonate use (5.8% vs 17.3%, p < 0.001) were lower in CaMos. The proportion of men with MOF who received bisphosphonates was below 10% in both cohorts.ConclusionHigher BMD and lower fracture prevalence were noted in the more recently recruited CLSA cohort compared to CaMos, even after adjusting for multiple covariates. We noted an increase in bisphosphonate use in the recent cohort, but it remained very low in men.

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Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures.

Publications

Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures.

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