Metabolic syndrome and the progression of knee osteoarthritis on MRI.

OBJECTIVE: Metabolic osteoarthritis (OA) is one of the proposed clinical phenotypes defined by the existence of metabolic syndrome (MetS). This study aimed to (1) investigate whether MetS and its components are associated with progression of knee OA magnetic resonance imaging (MRI) features, and (2) to evaluate the interaction of MetS with menopause and progression of MRI features. METHOD: 682 women from the Rotterdam Study who participated in a sub-study with knee MRI data available and 5-year follow-up were included. Tibiofemoral (TF) and patellofemoral (PF) OA features were assessed with the MRI Osteoarthritis Knee Score. MetS was quantified by the MetS severity Z-score. Generalized estimating equations were used to evaluate associations between MetS and menopausal transition and progression of MRI features. RESULTS: MetS severity at baseline was associated with progression of osteophytes in all compartments, bone marrow lesions (BMLs) in the PF compartment, and cartilage defects in the medial TF compartment. Waist circumference was associated with progression of osteophytes in all compartments and cartilage defects in the medial TF compartment. High-density lipoprotein (HDL)-cholesterol levels were associated with progression of osteophytes in the medial and lateral TF compartment and glucose levels with osteophytes in the PF and medial TF compartment. No interactions were found between MetS with menopausal transition and MRI features. CONCLUSION: Women with higher MetS severity at baseline showed progression of osteophytes, BMLs, and cartilage defects, indicating more structural knee OA progression after 5 years. Further studies are required to understand whether targeting MetS components may prevent the progression of structural knee OA in women.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Skin autofluorescence, a non-invasive biomarker of advanced glycation end products, and its relation to radiographic and MRI based osteoarthritis.

OBJECTIVES: Accumulation of advanced glycation end products (AGEs) in articular cartilage during aging has been proposed as a mechanism involved in the development of osteoarthritis (OA). Therefore, we investigated a cross-sectional relationship between skin AGEs, a biomarker for systemic AGEs accumulation, and OA. METHODS: Skin AGEs were estimated with the AGE Reader™ as skin autofluorescence (SAF). Knee and hip X-rays were scored according to Kellgren and Lawrence (KL) system. KL-sum score of all four joints was calculated per participant to assess severity of overall radiographic OA (ROA) including or excluding those with prosthesis. Knee MRI of tibiofemoral joint (TFMRI) was assessed for cartilage loss. Sex-stratified regression models were performed after testing interaction with SAF. RESULTS: 2,153 participants were included for this cross-sectional analysis. In women (n = 1,206) for one unit increase in SAF, the KL-sum score increased by 1.15 (95% confidence interval = 1.00-1.33) but excluding women with prosthesis, there was no KL-sum score increase [0.96 (0.83-1.11)]. SAF was associated with higher prevalence of prosthesis [Odds ratio, OR = 1.67 (1.10-2.54)] but not with ROA [OR = 0.83 (0.61-1.14)] when compared to women with no ROA. In men (n = 947), there was inconclusive association between SAF and KL sum score or prosthesis. For TFMRI (n = 103 women), SAF was associated with higher prevalence of cartilage loss, full-thickness [OR = 5.44 (1.27-23.38)] and partial-thickness [OR = 1.45 (0.38-5.54)], when compared to participants with no cartilage loss. CONCLUSION: Higher SAF in women was associated with higher prosthesis prevalence and a trend towards higher cartilage loss on MRI. Our data presents inconclusive results between SAF and ROA in both sexes.

The prevalence, incidence, and progression of radiographic thumb base osteoarthritis in a population-based cohort: the Rotterdam Study.

OBJECTIVE: To describe the prevalence, incidence, and progression of radiographic thumb carpometacarpal (CMC-1) and trapezioscaphoid (TS) radiographic osteoarthritis (ROA) in the general Dutch population aged ≥55y. DESIGN: Data were from the first and second cohort of the Rotterdam Study (1990-2005, 4-12 years follow-up, age 55+). Participants underwent bilateral radiographs at baseline (N = 7792) and follow-up (N = 3804), read for Kellgren-Lawrence (K-L) grade. ROA was defined on the joint level as K-L grade ≥2. The prevalence was assessed at baseline, incidence at follow-up in those free of ROA at baseline, and progression in those with ROA. Differences based on sex and age were evaluated using logistic regression models. RESULTS: At baseline, 1977 (25.3%) had CMC-1 ROA and 1133 (14.5%) TS ROA. The prevalence was higher in females for CMC-1 (aOR = 1.98 95%CI [1.77-2.21]) and TS ROA (aOR = 2.00 [1.74-2.29]) and increased for every year of age (CMC-1 ROA 1.08 [1.07-1.08]) (TS ROA 1.06 [1.05-1.07]). Most (437/512; 85.4%) incident cases of CMC-1 ROA (2994 at risk) were mild (K-L = 2), whereas most (145/167; 86,8%) incident cases of TS ROA (3311 at risk) were moderate to severe (K-L = 3/4). CMC-1 ROA progression was mostly (88/100; 88.0%) seen in the K-L 2 group at baseline, whereas that was (4/17; 23.5%) for TS ROA. CONCLUSION: CMC-1 ROA and TS ROA are prevalent in the general Dutch population. While incident CMC-1 ROA was primarily mild, incident TS ROA was more often moderate to severe. CMC-1 ROA was a strong predictor for incident TS ROA.

Characterization of dynamic changes in Matrix Gla Protein (MGP) gene expression as function of genetic risk alleles, osteoarthritis relevant stimuli, and the vitamin K inhibitor warfarin.

OBJECTIVE: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. METHODS: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1ß; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. RESULTS: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. DISCUSSION & CONCLUSIONS: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Retinal oximetry and fractal analysis of capillary maps in sickle cell disease patients and matched healthy volunteers.

PURPOSE: Fractal analysis can be used to quantitatively analyze the retinal microvasculature and might be a suitable method to quantify retinal capillary changes in sickle cell disease (SCD) patients. Retinal oximetry measurements might function as a proxy for the pathophysiology of cerebrovascular diseases. Moreover, hypoxia has an important role in the pathophysiology of diabetic and other retinopathies. However, little is known about the oximetry around the macula in SCD patients. With this study, we explored the feasibility to perform these quantified measurements in SCD patients. METHODS: Retinal microvascular and oximetry measurements were performed in eight SCD patients and eight healthy matched controls. Oximetry pictures and non-invasive capillary perfusion maps (nCPM) were obtained by the retinal function imager. Measurements were conducted twice on two different study days. Measured variables included monofractal dimension (Dbox), relative saturation, deoxygenated hemoglobin (deoxyHb), and oxygenated hemoglobin (oxyHb) concentration. RESULTS: No statistically significant differences in vessel density were found in the different annular zones (large vessels, p = 0.66; small vessels, p = 0.66) and anatomical quadrants (large vessels, p = 0.74; small vessels, p = 0.72). Furthermore, no significant between-group differences were found in the other different anatomical quadrants and annular zones around the fovea for relative saturation levels and deoxygenated Hb. However, the oxyHb levels were significantly lower in SCD patients, compared with those in matched controls in the temporal quadrants (p = 0.04; p = 0.02) and the superior nasal quadrant (p = 0.05). CONCLUSIONS: Our study demonstrated the feasibility of multispectral imaging to measure retinal changes in oxygenation in both SCD patients and matched volunteers. The results suggest that in SCD patients before any structural microvascular changes in the central retina are present, functional abnormalities can be observed with abnormal oximetry measurements.

Correction to: Retinal oximetry and fractal analysis of capillary maps in sickle cell disease patients and matched healthy volunteers.

In the published online PDF version, Figure 3 was incorrectly captured the same as Figure 1.

Development of a prediction model for future risk of radiographic hip osteoarthritis.

OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Osteoarthritis year in review 2016: genetics, genomics and epigenetics.

The purpose of this narrative review is to provide an overview of last year's publications in the field of genetics, genomics and epigenetics in the osteoarthritis (OA) field. Major themes arising from a Pubmed search on (epi)genetics in OA were identified. In addition, general developments in the fast evolving field of (epi)genetics are reviewed and relevance for the OA field is summarized. In the last 5 years, a number of genome-wide association studies have identified a modest number of genetic loci associated to OA. Continued functional research into these DNA variants is showing putative biological mechanisms underlying these associations. Over the last year, no additional large genome-wide association studies were published, but there clearly remains much to be discovered in the OA genetic field. A lot of research has been done into the epigenetics of OA over the last year. Several genome-wide screens examining the methylome of osteoarthritic cartilage were done. Pathway analysis confirmed deregulation of developmental and extracellular pathways in OA cartilage. Over the last year many microRNAs (miRNAs) have been identified that potentially play important roles in cartilage homeostasis and/or OA process. Continued research will learn whether these identified miRNAs are truly causal and can be used in clinical applications. Many of the epigenetic findings need further confirmation, but they highlight potential novel pathways involved in cartilage biology and OA.

Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.

Disability and not osteoarthritis predicts cardiovascular disease: a prospective population-based cohort study.

BACKGROUND: Previous studies found an association between osteoarthritis (OA) and risk of cardiovascular disease (CVD) and therefore suggested intensive treatment of cardiovascular risk factors in OA patients. However, prospective population-based data is lacking. OBJECTIVES: To investigate the association between OA and CVD longitudinally in a general population and examine the role of disability in this association. METHODS: This study was embedded in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands that started in 1989. At baseline 4648 persons aged ≥55, free of CVD were classified into those with and those without radiographic or clinical OA. HRs adjusted for traditional cardiovascular risk factors for developing CVD (a composite of fatal and non-fatal coronary heart disease and stroke) were calculated. RESULTS: During a median follow-up of 14.4 years, 1230 cardiovascular events occurred, of which 101 were in participants with clinical OA. Presence of radiographic OA at baseline was not related to future CVD (HR 0.99, 95% CI 0.86 to 1.15), neither was presence of clinical OA (HR 1.09, 95% CI 0.88 to 1.34). However, persons with increasing disability were more likely to suffer a cardiovascular event compared with non-disabled persons (HR 1.26, 95% CI 1.12 to 1.42); this was independent of the presence of OA. CONCLUSIONS: In this large population-based study, participants with OA were not at increased risk of CVD. The close relation between disability and osteoarthritis may explain previous findings. Further studies are required in order to clarify whether OA patients need more intensive treatment of their cardiovascular risk factors.

Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors.

OBJECTIVE: To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction. METHODS: The prognostic model was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study. RESULTS: In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study. CONCLUSIONS: Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.

Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women.

BACKGROUND: Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. OBJECTIVE: To study associations between the d3-GHR polymorphism and symptomatic OA. METHODS: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. RESULTS: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. CONCLUSIONS: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site.

Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis.

OBJECTIVE: To evaluate the role of three cartilage-derived biomarkers on osteoarthritis (OA): urinary C-terminal telopeptide (uCTX-II), serum cartilage oligomeric protein (sCOMP), and serum MMP degraded type II collagen (sC2M). SUBJECTS AND METHODS: Samples from 3582 individuals from the Rotterdam Study, the Genetics osteoArthritis and Progression (GARP), the Chingford Study and the TwinsUK cohort were assayed using enzyme-linked immune sorbent assays. Log10 of concentration levels were correlated with risk of hip, hand and knee OA, hip and knee OA severity and incidence, and progression of knee OA, adjusting for age, gender and body mass index (BMI). Results were meta-analysed to assess overall significance. RESULTS: After adjusting for covariates, sCOMP was associated with knee OA and hip and knee OA incidence. Furthermore, sC2M was associated with knee OA incidence and progression. After adjustment for multiple tests (Bonferroni P < 0.002) only the association between sCOMP and knee OA remained significant (odds ratio (OR) = 3.26 (95%CI 1.63-10.1) P = 0.0008 for each standard deviation (SD) increase in biomarker levels). Levels of uCTX-II were significantly associated with risk of hand, hip and knee OA, progression and incidence of knee OA. A receiver operating characteristics (ROC) analysis showed a consistent improvement in prediction of knee OA progression from an average area under the curve (AUC) is 0.646 for age, sex and BMI alone to an AUC = 0.668 including uCTX-II for prediction. CONCLUSIONS: uCTX-II is the most informative biochemical marker for prediction of OA. Both sCOMP and C2M showed some association with OA, thus indicating that they are descriptive of disease activity.

Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study.

UNLABELLED: Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. INTRODUCTION: Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort. METHODS: At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years). RESULTS: CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02-1.11], hip fractures (HR = 1.09; 1.02-1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14-1.58]. An inverse relationship between CRP levels and section modulus (-0.011 cm(3); -0.020 to -0.003 cm(3)) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 × 10(-56)), but not with fracture risk (HR = 1.00; 0.99-1.00; p = 0.23). CONCLUSIONS: Serum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness.

BACKGROUND AND AIMS: Hyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated. METHODS AND RESULTS: Baseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine-gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels. CONCLUSION: Homocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.

Cohort profile: Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) - an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis.

PURPOSE: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. PARTICIPANTS: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. FINDINGS TO DATE: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants. FUTURE PLANS: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip.

The contribution of hip geometry to the prediction of hip osteoarthritis.

OBJECTIVE: To determine how well measures of hip geometry can predict radiological incident hip osteoarthritis (HOA) compared to well known clinical risk factors. DESIGN: The study population is part of the Rotterdam Study, a prospective population-based cohort. Baseline pelvic radiographs were used to measure hip geometry by two methods: Statistical Shape Models (SSM) and predefined geometry parameters (PGPs). Incident HOA (Kellgren and Lawrence (KL) ≥ 2) was assessed in 688 participants after 6.5 years without radiographic HOA at baseline. The ability to predict HOA was quantified using the area under the Receiver Operating Characteristics (ROC) curve (AUC). RESULTS: Comparison of the two methods showed that both contain information that is not captured by the other method. At 6.5 years follow-up 132 hips had incident HOA. Five PGPs (Wiberg angle, Neck Width (NW), Pelvic Width (PW), Hip Axis Length (HAL) and Triangular Index (TI)) and two SSM (modes 5 and 9) were significant predictors of HOA (P = 0.007). Hip geometry added 7% to the prediction obtained by clinical risk factors (AUC = 0.67 (geometry), 0.66 (gender, age, Body Mass Index (BMI)) and combining both: AUC = 0.73, respectively). Mode 12 (associated with position of the femoral head in acetabulum) and Wiberg angle were predictors of HOA in participants without radiological signs at baseline (KL = 0). Although the strength of the prediction decreased for all variables at a longer follow-up, the contribution of hip geometry was still significant (P = 0.01). CONCLUSIONS: Hip geometry has a moderate ability to predict HOA in participants with and without initial signs of osteoarthritis (OA), similar to and largely independent of the predictive value of clinical risk factors.