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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.

ABSTRACT: Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹?; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹?; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

SUBMITTER: Paternoster L

PROVIDER: S-EPMC3578773 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.

Paternoster Lavinia L Lorentzon Mattias M Lehtimäki Terho T Eriksson Joel J Kähönen Mika M Raitakari Olli O Laaksonen Marika M Sievänen Harri H Viikari Jorma J Lyytikäinen Leo-Pekka LP Mellström Dan D Karlsson Magnus M Ljunggren Osten O Grundberg Elin E Kemp John P JP Sayers Adrian A Nethander Maria M Evans David M DM Vandenput Liesbeth L Tobias Jon H JH Ohlsson Claes C

PLoS genetics 20130221 2

Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortic ...[more]

PMID: 23437003

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Project description:BackgroundThe quality of the vertebral body structures such as endplate, cortex, and trabecular bone is important for understanding the performance of implants, particularly at the bone-implant interface. Although vertebral body structures have been analyzed separately in the literature, there is no comprehensive study to assess these anatomical measurements along with their interrelationships in the lumbar spine. Therefore, the purpose of this study was to assess variations in trabecular microstructure, vertebral endplate thickness and concavity, and vertebral body cortex thickness within the lumbar spine.MethodsA total of 80 lumbar vertebrae (L1-L5) were dissected from 16 human cadaver specimens and imaged with microcomputed tomography to determine trabecular microstructure, vertebral cortex thickness, endplate thickness, and maximum endplate concavity depth. A paired t test and regression analysis were used to determine significant differences (P < .05) between different vertebral levels and correlations between the analyzed anatomical parameters.ResultsL1 vertebra had significantly better (P?<?.02) trabecular bone microstructure (eg, trabecular bone volume fraction) than all other lumbar vertebrae. However, L1 vertebra also had significantly thinner (P???.02) anterior, left, and right cortices compared to all other vertebral levels. Within L3-L5 intervertebral disc spaces, cranial endplates had significantly greater (P???.03) thickness and maximum concavity depth compared to their respective caudal endplates. No strong correlations were observed between trabecular bone microstructure, maximum endplate concavity depth, vertebral cortex, and endplate thickness parameters.ConclusionsDetailed reference data of these anatomical parameters for each lumbar vertebral body can aid in improved understanding of bone quality, particularly when assessing different implant designs and fixation approaches. Moreover, such anatomical knowledge may help clinicians with optimal implant design selection and surgical placement of these devices into their respective locations.

Project description:BackgroundUnderstanding cellular structure and organization, which plays an important role in biological systems ranging from mechanosensation to neural organization, is a complicated multifactorial problem depending on genetics, environmental factors, and stochastic processes. Isolating these factors necessitates the measurement and sensitive quantification of many samples in a reliable, high-throughput, unbiased manner. In this manuscript we present a pipelined approach using a fully automated framework based on Synchrotron-based X-ray Tomographic Microscopy (SRXTM) for performing a full 3D characterization of millions of substructures.ResultsWe demonstrate the framework on a genetic study on the femur bones of in-bred mice. We measured 1300 femurs from a F2 cross experiment in mice without the growth hormone (which can confound many of the smaller structural differences between strains) and characterized more than 50 million osteocyte lacunae (cell-sized hollows in the bone). The results were then correlated with genetic markers in a process called quantitative trait localization (QTL). Our findings provide a mapping between regions of the genome (all 19 autosomes) and observable phenotypes which could explain between 8-40 % of the variance using between 2-10 loci for each trait. This map shows 4 areas of overlap with previous studies looking at bone strength and 3 areas not previously associated with bone.ConclusionsThe mapping of microstructural phenotypes provides a starting point for both structure-function and genetic studies on murine bone structure and the specific loci can be investigated in more detail to identify single gene candidates which can then be translated to human investigations. The flexible infrastructure offers a full spectrum of shape, distribution, and connectivity metrics for cellular networks and can be adapted to a wide variety of materials ranging from plant roots to lung tissue in studies requiring high sample counts and sensitive metrics such as the drug-gene interactions and high-throughput screening.

Project description:Accurate quantification of bone microstructure plays a significant role in understanding bone mechanics and response to disease or treatment. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows for the quantification of trabecular and cortical structure in vivo, with the capability of generating images at multiple voxel sizes (41, 82, and 123 μm). The aim of this study was to characterize the effect of voxel size on structural measures of trabecular and cortical bone and to determine accuracy in reference to micro-CT ([micro sign]CT), the gold standard for bone microstructure quantification.Seventeen radii from human cadaver specimens were imaged at each HR-pQCT voxel size and subsequently imaged using [micro sign]CT. Bone density and microstructural assessment was performed in both the trabecular and cortical compartments, including cortical porosity quantification. Two distinct analysis techniques were applied to the 41 μm HR-pQCT data: the standard clinical indirect analysis and a direct analysis requiring no density or structural model assumptions. Analysis parameters were adjusted to enable segmentation and structure extraction at each voxel size.For trabecular microstructural measures, the 41 μm HR-pQCT data displayed the strongest correlations and smallest errors compared to [micro sign]CT data. The direct analysis technique applied to the 41 μm data yielded an additional improvement in accuracy, especially for measures of trabecular thickness. The 123 μm data performed poorly, with all microstructural measures either having moderate or nonsignificant correlations with [micro sign]CT data. Trabecular densitometric measures showed strong correlations to [micro sign]CT data across all voxel sizes. Cortical thickness was strongly correlated with [micro sign]CT values across all HR-pQCT voxel sizes. The accuracy of cortical porosity parameters was highly dependent on voxel size; again, the 41 μm data was most strongly correlated. Measures of cortical density and pore diameter at all HR-pQCT voxel sizes had either weak or nonsignificant correlations.This study demonstrates the effect of voxel size on the accuracy of HR-pQCT measurements of trabecular and cortical microstructure and presents parameters for HR-pQCT analysis at nonstandard resolutions. For all parameters measured, correlations were strongest at 41 μm. Weak correlations for porosity measures indicate that a better understanding of pore structure and resolution dependence is needed.

Dataset Information

Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.

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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.

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