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.

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.

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.

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.

Lifestyle factors and metabolomic aging biomarkers: Meta-analysis of cross-sectional and longitudinal associations in three prospective cohorts.

Biological age uses biophysiological information to capture a person's age-related risk of adverse outcomes. MetaboAge and MetaboHealth are metabolomics-based biomarkers of biological age trained on chronological age and mortality risk, respectively. Lifestyle factors contribute to the extent chronological and biological age differ. The association of lifestyle factors with MetaboAge and MetaboHealth, potential sex differences in these associations, and MetaboAge's and MetaboHealth's sensitivity to lifestyle changes have not been studied yet. Linear regression analyses and mixed-effect models were used to examine the cross-sectional and longitudinal associations of scaled lifestyle factors with scaled MetaboAge and MetaboHealth in 24,332 middle-aged participants from the Doetinchem Cohort Study, Rotterdam Study, and UK Biobank. Random-effect meta-analyses were performed across cohorts. Repeated metabolomics measurements had a ten-year interval in the Doetinchem Cohort Study and a five-year interval in the UK Biobank. In the first study incorporating longitudinal information on MetaboAge and MetaboHealth, we demonstrate associations between current smoking, sleeping ≥8 hours/day, higher BMI, and larger waist circumference were associated with higher MetaboHealth, the latter two also with higher MetaboAge. Furthermore, adhering to the dietary and physical activity guidelines were inversely associated with MetaboHealth. Lastly, we observed sex differences in the associations between alcohol use and MetaboHealth.

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.

First-trimester maternal renin-angiotensin-aldosterone system activation and the association with maternal telomere length after natural and IVF/ICSI conceived pregnancies: the Rotterdam periconception cohort.

OBJECTIVE: To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI. METHODS: In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA. RESULTS: A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies. CONCLUSION: The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation.

Development of radiological knee osteoarthritis in patients with knee complaints.

OBJECTIVES: It is currently impossible to identify which patients with knee complaints presenting to the general practitioner will develop knee osteoarthritis (OA) pathology at a later stage. This study examines the determinants for developing OA pathology on x-ray in patients with knee complaints but no radiological OA at baseline in the painful knee. METHODS: Data from the prospective Rotterdam cohort study (including subjects aged ≥55 years) were used. Analysis was performed on 623 subjects with knee complaints at baseline and their data at 6-year follow-up (T1; n=607) and at 11-year follow-up (T2; n=457). At baseline, none had radiological OA (rOA=Kellgren and Lawrence (KL) grade ≥2) in the painful joint. At follow-up, predictors for rOA were determined using multivariate ordinal logistic regression analysis. RESULTS: At T1, 8.5% of the group had developed knee rOA and, by T2, this had increased to 23%. Determinants remaining significant in the multivariate analysis were female gender (OR 1.95, 95% CI 1.15 to 3.36), other joint complaints (OR 2.22, 95% CI 1.12 to 4.35) and KL grade 1 at baseline in the painful knee joint (OR 7.14, 95% CI 4.55 to 11.1). All outcomes are adjusted for all included determinants. CONCLUSION: The best predictors of development of knee rOA are a combination of female gender, other joint complaints and KL grade 1 in the painful joint. KL grade 1 in combination with knee pain should be considered as early OA in patient management.

Osteoarthritis year 2012 in review: genetics and genomics.

The field of genetics and genomics is a highly technological driven field that is advancing fast. The purpose of this year in review of genetics and genomics was to highlight the publications that apply these new technologies tools to improve understanding of the pathophysiology of osteoarthritis (OA). In addition, most recent developments in genetics and genomics research and their relevance to OA are discussed in this review.

Association between spinal morning stiffness and lumbar disc degeneration: the Rotterdam Study.

OBJECTIVE: To explore the associations between spinal morning stiffness and lumbar disc degeneration (LDD). DESIGN: Data from a cross-sectional general population-based study (Rotterdam Study-I) were used. Intervertebral disc spaces and osteophytes of people aged ≥55 years were scored on lumbar lateral radiographs (L1-2 through L5-S1 was scored). Logistic regression analysis was used to explore associations between spinal morning stiffness and two definitions of LDD (i.e., 'narrowing' and 'osteophytes'). Spinal morning stiffness combined with low back pain and its association with LDD was also analyzed. Similar analyses were performed for knee and hip pain, morning stiffness in the legs, and radiographic knee and hip osteoarthritis (OA) in order to compare these associations with those of LDD. All analyses were adjusted for age, gender, and body mass index (BMI). RESULTS: Lumbar lateral radiographs were scored for 2,819 participants. Both definitions of LDD were associated with spinal morning stiffness: adjusted odds ratio (aOR) 1.3; 95% confidence interval (CI): 1.1-1.6 for 'osteophytes' and aOR 1.8; 95% CI: 1.4-2.2 for 'narrowing'. Both the odds ratios increased when spinal morning stiffness was combined with low back pain: aOR 1.5; 95% CI: 1.1-2.0 for 'osteophytes' and aOR 2.5; 95% CI: 1.9-3.4 for 'narrowing'. When morning stiffness in the legs was combined with knee or hip pain, the associations with radiographic knee or hip OA were: aOR 3.0; 95% CI: 2.1-4.1 for knee OA and aOR 3.1; 95% CI: 1.9-5.0 for hip OA. CONCLUSIONS: Reported spinal morning stiffness is associated with LDD. The associations increased when we combined spinal morning stiffness with low back pain. The magnitude of the association for the definition 'narrowing' is similar to the association between morning stiffness in the legs and knee or hip OA.

Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis.

OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1ß (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.

Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium.

OBJECTIVE: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. METHODS: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. RESULTS: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. CONCLUSION: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.