Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape.
ABSTRACT: OBJECTIVE:To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits. METHODS:We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome-wide association study. We built 3 SSMs capturing the shape variation of the OA-unaffected proximal femur in the entire mixed-sex cohort and for male/female-stratified cohorts. We selected 41 candidate single-nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype-phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes. RESULTS:The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P?=?0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed-sex SSM (P?=?0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed-sex SSM (P?=?0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA. CONCLUSION:These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
Project description:To test whether single-nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape, and to determine whether FRZB variant alleles affect the relationship between hip shape and radiographic osteoarthritis (OA) of the hip.A nested case-control study of Caucasian women, age ?65 years, from the Study of Osteoporotic Fractures cohort was performed. Cases (n = 451) were defined as subjects with radiographic evidence of incident hip OA during followup, while controls (n = 601) were subjects in whom no radiographic hip OA was identified at baseline or followup. Statistical shape modeling (SSM) of the digitized hip radiographs was performed to assess the shape of the proximal femur, using 10 independent modes of shape variation generated by principal components analysis. In addition, center-edge angle and acetabular depth were assessed as geometric measurements of acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and radiographic hip OA was analyzed using a logistic regression model with or without inclusion of interaction terms.The rs288326 and rs7775 alleles were associated with the shape of the proximal femur (SSM mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (SSM mode 2) in predicting radiographic hip OA (P for interaction = 0.022). Among subjects with the rs288326 variant allele, there was an increased likelihood of radiographic hip OA in association with increasing quartiles of proximal femur shape mode 2 (for the fourth quartile of mode 2, odds ratio 2.5, 95% confidence interval 1.15, 5.25; P for linear trend = 0.02).The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident radiographic hip OA. These findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA.
Project description:Statistical shape models (SSMs) are a well established computational technique to represent the morphological variability spread in a set of matching surfaces by means of compact descriptive quantities, traditionally called "modes of variation" (MoVs). SSMs of bony surfaces have been proposed in biomechanics and orthopedic clinics to investigate the relation between bone shape and joint biomechanics. In this work, an SSM of the tibio-femoral joint has been developed to elucidate the relation between MoVs and bone angular deformities causing knee instability. The SSM was built using 99 bony shapes (distal femur and proximal tibia surfaces obtained from segmented CT scans) of osteoarthritic patients. Hip-knee-ankle (HKA) angle, femoral varus-valgus (FVV) angle, internal-external femoral rotation (IER), tibial varus-valgus (TVV) angles, and tibial slope (TS) were available across the patient set. Discriminant analysis (DA) and logistic regression (LR) classifiers were adopted to underline specific MoVs accounting for knee instability. First, it was found that thirty-four MoVs were enough to describe 95% of the shape variability in the dataset. The most relevant MoVs were the one encoding the height of the femoral and tibial shafts (MoV #2) and the one representing variations of the axial section of the femoral shaft and its bending in the frontal plane (MoV #5). Second, using quadratic DA, the sensitivity results of the classification were very accurate, being all >0.85 (HKA: 0.96, FVV: 0.99, IER: 0.88, TVV: 1, TS: 0.87). The results of the LR classifier were mostly in agreement with DA, confirming statistical significance for MoV #2 (p = 0.02) in correspondence to IER and MoV #5 in correspondence to HKA (p = 0.0001), FVV (p = 0.001), and TS (p = 0.02). We can argue that the SSM successfully identified specific MoVs encoding ranges of alignment variability between distal femur and proximal tibia. This discloses the opportunity to use the SSM to predict potential misalignment in the knee for a new patient by processing the bone shapes, removing the need for measuring clinical landmarks as the rotation centers and mechanical axes.
Project description:<h4>Objective</h4>Statistical shape modelling (SSM) of hip dual-energy X-ray absorptiometry (DXA) scans has identified relationships between hip shape and radiographic hip OA (rHOA). We aimed to further elucidate shape characteristics related to rHOA by focusing on subregions identified from whole-hip shape models.<h4>Method</h4>SSM was applied to hip DXAs obtained in the Osteoporotic Fractures in Men Study. Whole-hip shape modes (HSMs) associated with rHOA were combined to form a composite at-risk-shape. Subsequently, subregional HSMs (cam-type and lesser trochanter modes) were built, and associations with rHOA were examined by logistic regression. Subregional HSMs were further characterised, by examining associations with 3D-HSMs derived from concurrent hip CT scans.<h4>Results</h4>4,098 participants were identified with hip DXAs and radiographs. Composite shapes from whole-hip HSMs revealed that lesser trochanter size and cam-type femoral head are related to rHOA. From sub-regional models, lesser trochanter mode (LTM)1 [OR 0.74; 95%CI 0.63.0.87] and cam-type mode (CTM)3 [OR 1.27; 220.127.116.11] were associated with rHOA, associations being similar to those for whole hip HSMs. 515 MrOS participants had hip DXAs and 3D-HSMs derived from hip CT scans. LTM1 was associated with 3D-HSMs that also represented a larger lesser trochanter [3D-HSM7 (beta (β)-0.23;-0.33,-0.14) and 3D-HSM9 (β0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (β-0.16;-0.25,-0.07) and 3D-HSM6 (β 0.19; 0.10.0.28)].<h4>Conclusion</h4>Subregional SSM of hip DXA scans suggested larger lesser trochanter and cam morphology underlie associations between overall hip shape and rHOA. 3D hip modelling suggests our subregional SSMs represent true anatomical variations in hip shape, warranting further investigation.
Project description:Hip shape is an important determinant of hip osteoarthritis (OA), which occurs more commonly in women. However, it remains unclear to what extent differences in OA prevalence are attributed to sex differences in hip shape. Here, we explore sex differences in proximal femur shape in a cohort of adolescents. Hip morphology was quantified using hip DXA scans from the Avon Longitudinal Study of Parents and Children. Independent modes of variation (hip shape mode (HSM) scores) were generated for each image using an adult reference statistical shape model (N?=?19,379). Linear regression was used to examine sex differences for the top ten HSMs, adjusting for age, height, lean and fat mass. Complete outcome and covariate data were available for 4,428 and 4,369 participants at ages 14 and 18 years, respectively. Several HSMs showed sex differences at both time points. The combined effect of sex on hip shape at age 14 reflected flatter femoral head and smaller lesser trochanter in females compared with males and, following adjustment for age and body size, these differences became more pronounced. At age 18, smaller lesser trochanter and femoral neck width (FNW) in females still remained although differences in femoral head, femoral shaft and FNW were largely attenuated following adjustment. Sexual dimorphism in proximal femur shape can be discerned in adolescence and early adulthood. Observed differences in proximal femur shape, particularly at age 14 were largely independent of body size, however to what extent differences in hip shape in early life play a role in predisposing to hip OA in later life remains to be determined.
Project description:OBJECTIVE:To examine the relationship between pubertal timing (using measures of height tempo) and proximal femur shape in a large adolescent cohort. METHODS:Hip DXA scans were obtained in offspring from the Avon Longitudinal Study of Parents and Children. To quantify hip morphology, the images were analyzed using Shape software based on a 53-point statistical shape model and independent modes of variation (hip shape mode (HSM) scores) for each image were generated. Height tempo (which corresponds to age at peak height velocity (aPHV)) was estimated from serial height measurements collected between age 5-20 years. Multivariable linear regression was used to examine cross-sectional associations between height tempo and the top ten HSMs at age 14 and 18, adjusting for sex and fat mass index (FMI). RESULTS:Complete outcome and covariate data were available from 3827 and 3507 participants at age 14 and 18 years, respectively. Mean aPHV was 13.5 and 11.8 years for males and females, respectively. At age 14, height tempo was associated with a majority of modes, except for HSM4 and there was strong evidence of interaction by sex. In males, all modes showed evidence of an association with tempo, independent of FMI, with the strongest observed for HSM8 (adjusted ? 0.38 (0.33, 0.43) p = 4.1 × 10-50). Compared with males, the associations were generally weaker in females, with the strongest effect observed for HSM8 (adjusted ? 0.10 (0.05, 0.14) p = 1.6 × 10-5). The overall effect of later pubertal timing on proximal femur shape in males was a narrower femoral neck and larger superolateral head, whereas in females these changes were hard to discern. When assessed at age 18, there was little relationship between tempo and proximal femur shape in either sex. CONCLUSION:Our results indicate that significant changes in hip shape occur during puberty, including aspects of shape which may be related to future risk of hip OA and/or fracture. However, puberty timing per se does not appear to exert long lasting effects on proximal femur shape.
Project description:<h4>Objective</h4>Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.<h4>Methods</h4>Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.<h4>Results</h4>Complete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p = 9.9 × 10<sup>-8</sup>; age 18: -0.05, p = 3.3 × 10<sup>-6</sup>) and HSM5 (age 14: beta -0.07, p = 1.6 × 10<sup>-4</sup>; age 18: -0.1, p = 2.7 × 10<sup>-6</sup>). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10<sup>-5</sup>; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p = 0.001; age 18: -0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.<h4>Conclusion</h4>In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.
Project description:We aimed to compare proximal femur geometry and biomechanics in postmenopausal women with osteoarthritis (OA) and/or osteoporosis (OP), using quantitative computed tomography (QCT). A retrospective analysis of QCT scans of the proximal femur of 175 postmenopausal women was performed. Morphometric and densitometric data of the proximal femur were used to evaluate its biomechanics. We found, 21 had a normal bone mineral density (BMD), 72 had osteopenia, and 81 were diagnosed with OP. Radiographic findings of hip OA were seen in 43.8%, 52.8%, and 39.5% of the normal BMD, osteopenic, and OP groups, respectively (<i>p</i> < 0.05). OA was significantly correlated with total hip volume (r = 0.21), intertrochanteric cortical volume (r = 0.25), and trochanteric trabecular volume (r = 0.20). In each densitometric group, significant differences in hip geometry and BMD were found between the OA and non-OA subgroups. Hip OA and OP often coexist. In postmenopausal women, these diseases coexist in 40% of cases. Both OA and OP affect hip geometry and biomechanics. OA does so regardless of densitometric status. Changes are mostly reflected in the cortical bone. OA leads to significant changes in buckling ratio (BR) in both OP and non-OP women.
Project description:Hip shape is a risk factor for the development of hip osteoarthritis (OA), and current methods to assess hip shape from radiographs are limited; therefore this study explored current and novel methods to assess hip shape.Data from a prior case-control study nested in the Johnston County OA Project were used, including 382 hips (from 342 individuals). Hips were classified by radiographic hip OA (RHOA) status as RHOA cases (baseline Kellgren Lawrence grade [KLG] 0 or 1, follow-up [mean 6 years] KLG ? 2) or controls (KLG = 0 or 1 at both baseline and follow-up). Proximal femur shape was assessed using a 60-point model as previously described. The current analysis explored commonly used principal component analysis (PCA), as well as novel statistical methodologies suited to high dimension low sample size settings (Distance Weighted Discrimination [DWD] and Distance Projection Permutation [DiProPerm] hypothesis testing) to assess differences between cases and controls.Using these novel methodologies, we were able to better characterize morphologic differences by sex and race. In particular, the proximal femurs of African American women demonstrated significantly different shapes between cases and controls, implying an important role for sex and race in the development of RHOA. Notably, discrimination was improved with the use of DWD and DiProPerm compared to PCA.DWD with DiProPerm significance testing provides improved discrimination of variation in hip morphology between groups, and enables subgroup analyses even under small sample sizes.