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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

ABSTRACT: Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n?=?15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n?=?21,701) and clinical vertebral fracture (n?=?5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]?=?3%) was associated with higher vBMD (??=?0.22, p?=?1.9?×?10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR]?=?0.75; false discovery rate [FDR] p?=?0.01). In 1p36.12, rs12742784 (MAF?=?21%) was associated with higher vBMD (??=?0.09, p?=?1.2?×?10-10 ) and decreased risk of clinical vertebral fracture (OR?=?0.82; FDR p?=?7.4?×?10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (??=?0.28, FDR p?=?0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (??=?0.12, FDR p?=?1.7?×?10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

SUBMITTER: Nielson CM

PROVIDER: S-EPMC5477772 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

Nielson Carrie M CM Liu Ching-Ti CT Smith Albert V AV Ackert-Bicknell Cheryl L CL Reppe Sjur S Jakobsdottir Johanna J Wassel Christina C Register Thomas C TC Oei Ling L Alonso Nerea N Oei Edwin H EH Parimi Neeta N Samelson Elizabeth J EJ Nalls Mike A MA Zmuda Joseph J Lang Thomas T Bouxsein Mary M Latourelle Jeanne J Claussnitzer Melina M Siggeirsdottir Kristin K Srikanth Priya P Lorentzen Erik E Vandenput Liesbeth L Langefeld Carl C Raffield Laura L Terry Greg G Cox Amanda J AJ Allison Matthew A MA Criqui Michael H MH Bowden Don D Ikram M Arfan MA Mellström Dan D Karlsson Magnus K MK Carr John J Budoff Matthew M Phillips Caroline C Cupples L Adrienne LA Chou Wen-Chi WC Myers Richard H RH Ralston Stuart H SH Gautvik Kaare M KM Cawthon Peggy M PM Cummings Steven S Karasik David D Rivadeneira Fernando F Gudnason Vilmundur V Orwoll Eric S ES Harris Tamara B TB Ohlsson Claes C Kiel Douglas P DP Hsu Yi-Hsiang YH

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20160906 12

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical ver ...[more]

PMID: 27476799

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Project description:PurposeTo establish and evaluate the diagnostic accuracy of volumetric bone mineral density (vBMD) threshold values at different spinal levels, derived from opportunistic quantitative computed tomography (QCT), for the prediction of incident vertebral fractures (VF).Materials and methodsIn this case-control study, 35 incident VF cases (23 women, 12 men; mean age: 67 years) and 70 sex- and age-matched controls were included, based on routine multi detector CT (MDCT) scans of the thoracolumbar spine. Trabecular vBMD was measured from routine baseline CT scans of the thoracolumbar spine using an automated pipeline including vertebral segmentation, asynchronous calibration for HU-to-vBMD conversion, and correction of intravenous contrast medium (https://anduin.bonescreen.de). Threshold values at T1-L5 were calculated for the optimal operating point according to the Youden index and for fixed sensitivities (60 - 85%) in receiver operating characteristic (ROC) curves.ResultsvBMD at each single level of the thoracolumbar spine was significantly associated with incident VFs (odds ratio per SD decrease [OR], 95% confidence interval [CI] at T1-T4: 3.28, 1.66-6.49; at T5-T8: 3.28, 1.72-6.26; at T9-T12: 3.37, 1.78-6.36; and at L1-L4: 3.98, 1.97-8.06), independent of adjustment for age, sex, and prevalent VF. AUC showed no significant difference between vertebral levels and was highest at the thoracolumbar junction (AUC = 0.75, 95%-CI = 0.63 - 0.85 for T11-L2). Optimal threshold values increased from lumbar (L1-L4: 52.0 mg/cm³) to upper thoracic spine (T1-T4: 69.3 mg/cm³). At T11-L2, T12-L3 and L1-L4, a threshold of 80.0 mg/cm³ showed sensitivities of 85 - 88%, and specificities of 41 - 49%. To achieve comparable sensitivity (85%) at more superior spinal levels, resulting thresholds were higher: 114.1 mg/cm³ (T1-T4), 92.0 mg/cm³ (T5-T8), 88.2 mg/cm³ (T9-T12).ConclusionsAt all levels of the thoracolumbar spine, lower vBMD was associated with incident VFs in an elderly, predominantly oncologic patient population. Automated opportunistic osteoporosis screening of vBMD along the entire thoracolumbar spine allows for risk assessment of imminent VFs. We propose level-specific vBMD threshold at the thoracolumbar spine to identify individuals at high fracture risk.

Project description:UNLABELLED:Daily teriparatide injections have been shown to reduce vertebral and non-vertebral fractures. Here, we demonstrate that the magnitude of fracture risk reduction is independent of baseline fracture probability assessed by FRAX. INTRODUCTION:Daily administration of 20 or 40 ?g teriparatide has been shown to significantly decrease the risk of vertebral and non-vertebral fracture compared with placebo. The aim of the present study was to evaluate fracture risk assessed at baseline using the FRAX® tool and to determine the efficacy of teriparatide as a function of baseline fracture risk. METHODS:One thousand six hundred thirty-seven postmenopausal women in the pivotal phase three trial, randomly assigned to receive placebo (n?=?544), teriparatide 20 ?g per day (n?=?541) or teriparatide 40 ?g per day (n?=?552), were studied. Baseline clinical risk factors were entered into country-specific FRAX models to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. Because there was no difference in effect of 20 and 40 ?g teriparatide daily on fracture occurrence, the two active groups were merged. The interaction between probability of a major fracture and treatment efficacy was examined by Poisson regression. RESULTS:The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.2-67.2 %. Treatment with teriparatide was associated with a 37 % decrease in all non-vertebral fractures (95 % CI 10-56 %) and a 56 % decrease in low-energy non-vertebral fractures (95 % CI 24-75 %) compared with placebo. The risk of morphometric vertebral fractures decreased significantly by 66 % (95 % CI 50-77 %). Hazard ratios for the effect of teriparatide on the fracture outcome did not change significantly with increasing fracture probability (p?>?0.30). Similar findings were noted for the interaction when BMD was excluded from the FRAX model, or when probability of hip fracture was used as the marker of baseline risk. CONCLUSION:We conclude that teriparatide significantly decreases the risk of non-vertebral and morphometric vertebral fractures in women by a similar extent, irrespective of baseline fracture probability.

Project description:RationaleFormer smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered.ObjectivesTo demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women.MethodsCharacteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use.Measurements and main resultsvBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures.ConclusionsMale smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

Dataset Information

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

Publications

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

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