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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 (β = 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 (β = 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 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 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:Vertebral fracture (VF) is a strong predictor of subsequent fracture. In this study of older women, VF, identified by dual-energy X-ray absorptiometry (DXA) vertebral fracture assessment (VFA), were associated with an increased risk of incident fractures and had a substantial impact on fracture probability, supporting the utility of VFA in clinical practice.PurposeClinical and occult VF can be identified using VFA with dual-energy X-ray absorptiometry (DXA). The aim of this study was to investigate to what extent VFA-identified VF improve fracture risk prediction, independently of bone mineral density (BMD) and clinical risk factors used in FRAX.MethodsA total of 2852 women, 75-80 years old, from the prospective population-based study SUPERB cohort, were included in this study. At baseline, BMD was measured by DXA, VF diagnosed by VFA, and questionnaires used to collect data on risk factors for fractures. Incident fractures were captured by X-ray records or by diagnosis codes. An extension of Poisson regression was used to estimate the association between VFA-identified VF and the risk of fracture and the 5- and 10-year probability of major osteoporotic fracture (MOF) was calculated from the hazard functions for fracture and death.ResultsDuring a median follow-up of 5.15 years (IQR 4.3-5.9 years), the number of women who died or suffered a MOF, clinical VF, or hip fracture was 229, 422, 160, and 124, respectively. A VFA-identified VF was associated with an increased risk of incident MOF (hazard ratio [HR] = 1.78; 95% confidence interval [CI] 1.46-2.18), clinical VF (HR = 2.88; 95% [CI] 2.11-3.93), and hip fracture (HR = 1.67; 95% [CI] 1.15-2.42), adjusted for age, height, and weight. For women at age 75 years, a VFA-identified VF was associated with 1.2-1.4-fold greater 10-year MOF probability compared with not taking VFA into account, depending on BMD.ConclusionIdentifying an occult VF using VFA has a substantial impact on fracture probability, indicating that VFA is an efficient method to improve fracture prediction in older women.

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:UnlabelledDaily 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.IntroductionDaily administration of 20 or 40 μg 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.MethodsOne thousand six hundred thirty-seven postmenopausal women in the pivotal phase three trial, randomly assigned to receive placebo (n = 544), teriparatide 20 μg per day (n = 541) or teriparatide 40 μg 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 μg 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.ResultsThe 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.ConclusionWe 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.

Project description:BackgroundFor osteoporotic fractures in men (MrOS) and in women (MsOS) (Hong Kong) baseline (BL) study, Chinese men and women ≥65 years were recruited during 2001 to 2003. This study presents the year-18 follow-up (FU) results. We were particularly interested in whether women with 'minimal' grade osteoporotic-like vertebral fracture (OLVF) of <20% height loss have an increased vertebral fracture (VF) risk than those without BL OLVF.MethodsAt year-18 FU, spine radiography was performed on 144 males (mean: 87.4±3.1 years) and 156 females (mean: 87.0±3.2 years). OLVF classification included no OLVF (grade 0), and OLVFs with <20%, ≥20-25%, ≥25%-1/3, ≥1/3-40%, ≥40%-2/3, ≥2/3 height loss (grades 1-6). With an existing OLVF, a further height loss of ≥15% was an OLVF progression. A new incident OLVF was a change from grade 0 to ≥ grade 2 or to grade 1 with the appearance of endplate and/or cortex fracture (ECF) during FU. Both OLVF progression and incident OLVF were considered incident VF. Acquired short vertebra (aSV) was defined as with decreased vertebral anterior and middle heights, while without anterior wedging and bi-concave changes, and only those with at least two adjacent aSVs were recorded as aSV cases.ResultsFor subjects without BL OLVF, 12.5% of the males and 27.1% of the females had incident VF. For subjects with BL OLVF of ≥20% height loss, males' and females' incident VF rate were 20% and 66.7% respectively. Females subjects with BL minimal OLVF, while all without radiographic ECF, had an incident VF rate of 59.3% during the FU. For males with and without aSV, 11.8% and 15% have incident fracture of other vertebrae. For females with and without aSV, 35.3% and 34.5% have incident fracture of other vertebrae. Recovery from minimal or mild grades OLVF to normal shape was observed in a number of cases.ConclusionsOLVF with less than 20% height loss is associated with increased VF risk in older females, but not in older males. Acquired short vertebra (SV) is not associated with increased incident fracture risk for other vertebrae, both for females and males. OLVF among older subjects can repair and heal.

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.

Similar Datasets

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