Prevalence, incidence, and re-occurrence risk of musculoskeletal pain in older adults in the United Kingdom: a population-based study.

Background: Throughout the literature, pain burden has been assessed by asking different questions, often cross-sectionally, different populations of interest. We know little about pain re-occurrence and how to translate knowledge between pain questions within the population of interest. We aimed to estimate the burden of musculoskeletal pain by estimating prevalence, incidence rates, and re-occurrence risk of back, hand, hip, knee, and foot pain using different questions from UK population-based samples and predict the number of affected individuals in the UK in 2030. Methods: We used two UK population-representative studies, with two eight-year-apart follow-ups and two pain questions assessing recent pain episodes and often troubled pain when walking. We estimated prevalence, 8-year incidence rates, and 8-year pain re-occurrence risk for women and men aged 50 years and older and the relation between the two pain questions. Results: Among UK individuals older than 50 years, the prevalence of musculoskeletal pain episode was 20%-50%, and the incidence was 20-40/1,000 person-years, while the prevalence of pain when walking was 10%-25%, and the incidence was 6-12/1,000 person-years. The most prevalent musculoskeletal pain types were back and knee pain; of five women experiencing back or knee pain episodes, three are expected to be often troubled by pain. Hip and foot pain had similar estimates in both questions. Hand pain peaked in women aged 50-65 years. Women had higher prevalence and incidence rates, but men had higher 8-year re-occurrence risk of all types of musculoskeletal pain. Reporting a pain episode was associated with two times higher risk, but often troubled by pain when walking was associated with four to seven times times higher risk of the same pain in 8 years. Women and men with a body mass index (BMI) of ≥27 kg/m2 were twice as likely to experience musculoskeletal pain than those with BMI<27 kg/m2. In 2030, we expect 2-7 million people older than 50 years in the United Kingdom to seek site-specific musculoskeletal pain-focused healthcare. Conclusions: In individuals older than 50 years, the experience of musculoskeletal pain at least doubles the chance of experiencing it again. Women report musculoskeletal pain more often, but men report more persistent pain. Musculoskeletal pain presents a significant burden to public health.

Effects of body weight and fat mass on back pain - direct mechanical or indirect through inflammatory and metabolic parameters?

BACKGROUND: While reports indicate the association between obesity and back pain, its mechanism is still unclear. Thus, we aimed to investigate the effects of weight and its components on back pain in middle-aged women while considering direct mechanical and indirect effects via inflammatory and metabolic parameters. METHODS: We used data from the Chingford 1000 Women Study, two follow-ups seven years apart. We assessed effects of weight, body mass index (BMI), total fat mass (TFM), total lean mass (TLM) and total bone mineral density (TBMD), measured by dual-energy X-ray absorptiometry, on back pain episode. We used inflammatory (C-reactive protein, interleukin-6, and tumour necrosis factor-alpha) and metabolic parameters (systolic and diastolic blood pressure, triglyceride, high-density lipoprotein cholesterol, and fasting blood glucose) as mediators of indirect effects. We investigated associations of interest cross-sectionally and longitudinally using binary logistic regression and parallel mediation model. RESULTS: We included 826 Chingford middle-aged women (mean age=60.7, SD=5.9) from the first used follow-up in cross-sectional and mediation analyses and 645 women that attended the follow-up seven years later, in longitudinal analyses. We found that increased weight was directly associated with increased odds of having back pain episode (OR=1.02; 95% CI 1.01-1.03), similarly as BMI (OR=1.05; 95% CI 1.02-1.08) and TFM (OR=1.03; 95% CI 1.01-1.04) consistently across the cross-sectional and longitudinal models, but not TLM or TBMD. However, we did not find consistent indirect effects of weight or its components through measured inflammatory or metabolic parameters on back pain. CONCLUSIONS: Our results show that in middle-aged women, weight, BMI and TFM are directly related to back pain, indicating prominence of mechanical loading effect.

Specific body mass index trajectories were related to musculoskeletal pain and mortality: 19-year follow-up cohort.

OBJECTIVE: We aimed to study 19-year body mass index (BMI) patterns and their (1) bidirectional relationship with musculoskeletal pain and (2) mortality risk. STUDY DESIGN AND SETTING: We used data from the Chingford study and group-based trajectory modelling to define 19-year BMI patterns. We investigated whether baseline back, hand, hip, and knee pain (as single- and multi-site) predicted 19-year BMI trajectory, and whether 19-year BMI patterns predicted pain in year 20. We explored BMI trajectories and mortality risk over 25 years (life expectancy). RESULTS: We included 938 women (mean age: year-1=54, year-20=72) and found seven distinct 19-year BMI trajectories: two normal-weighted (reference), slightly overweight, lower and upper overweight-to-obese, lower and upper obese. BMI patterns capturing the increase overweight-to-obese (BMI 27-34 overtime) were bidirectionally related to knee and multi-site pain. The lower obese pattern (BMI 33-38) was unidirectionally associated with lower limb pain. Women with BMI above 40 had an increased all-cause and cardiovascular mortality risk. CONCLUSION: For most postmenopausal women, the overweight WHO category was a transition. Two patterns capturing increase overweight-to-obese were mutually related to musculoskeletal pain, i.e., knee and multi-site pain contributed to becoming obese, and trajectories of becoming obese increased the odds of experiencing pain later.

Effect of Heeled Shoes on Joint Symptoms and Knee Osteoarthritis in Older Adults: A 5-Year Follow-Up Study.

OBJECTIVE: Our aims were to examine the effects of heeled shoes on incident knee osteoarthritis (OA) and joint pain. METHODS: We used longitudinal data from the Chingford 1000 Women Study (Chingford Study), a prospective cohort of women aged 50 years or older. Participants with musculoskeletal disorders and/or a history of knee-related injury/surgery were excluded. Participants were followed for up to 5 years for incident outcomes including 1) radiographic knee OA (RKOA) and 2) joint pain (feet, knees, hips, and back). Footwear data, including ever worn heels of 2 inches or more and daytime/evening hours (per week) spent wearing heeled shoes over five decades (ages <20 years, 20-30 years, 30-40 years, and >50 years), were available at Year 10 whereas knee radiographs and joint symptom data were also collected at Year 15. Cumulative time spent wearing heeled shoes was calculated for women reporting ever-use of heeled shoes (≥2 inches). Multiple logistic regression was used to examine the relationship between exposures and outcomes (from Year 10 to Year 15). RESULTS: A total of 356 women were eligible at Year 10 with a median (interquartile range) age of 60 (56-65) years. Compared with non-use, ever-use of heeled shoes (≥2 inches) was not associated with incident RKOA (1.35; 95% confidence interval: 0.56-3.27). No associations were observed between increasing cumulative time spent wearing heels and incident outcomes. CONCLUSION: Compared with the non-use of heeled shoes, ever-use of heels (≥2 inches) was not associated with incident RKOA and incident joint symptoms. Further, increasing cumulative time spent wearing heels was not associated with any of our outcomes.

Association of Lumbar Spine Radiographic Changes With Severity of Back Pain-Related Disability Among Middle-aged, Community-Dwelling Women.

Importance: Previous studies, using mostly cross-sectional data, provide conflicting evidence of an association between lumbar spine radiographic changes and the severity of back pain-related disability. Such conflicting evidence may be associated with widely unnecessary diagnostic imaging of the lumbar spine. Objective: To examine both cross-sectional and longitudinal associations between lumbar spine radiographic changes and the severity of back pain-related disability among middle-aged, community-dwelling women. Design, Setting, and Participants: This population-based prospective cohort study used data from the Chingford 1000 Women Study. Analyses included data collected from year 6 (1994-1996; physical activity was measured), year 9 (1997-1999; treated as baseline), and year 15 (2003-2005), with a total length of follow-up for longitudinal analyses of 6 years. Data were analyzed from April 17 to November 3, 2020. Exposures: Primary exposure was lumbar spine radiographic changes, defined using the Kellgren-Lawrence (K-L) grade. Secondary exposures were defined using presence of osteophytes and disc space narrowing. The composite score combined the number of lumbar spine segments with definite changes detected on radiographic images (ie, radiographic changes) (K-L grade ≥2, which means at least definite osteophyte and possible narrowing of disc space are present; osteophyte and disc space narrowing grade ≥1, which means at least mild or definite changes are present). Main Outcomes and Measures: Self-reported back pain-related disability measured in years 9 and 15 assessed by the St Thomas disability questionnaire. Results: Among 650 women (mean [SD] age, 61.3 [5.9] years) in cross-sectional analyses and 443 women (mean [SD] age, 60.6 [6.0] years) in longitudinal analyses, there was no evidence to support an association between higher number of lumbar segments with radiographic changes (K-L grade, osteophytes, and disc space narrowing) and more severe back pain-related disability (eg, cross-sectional analyses using the K-L grade; 1 segment vs 0 segment: adjusted odds ratio, 1.22 [95% CI, 0.76-1.96]). No interactions were found of an association between lumbar spine radiographic changes and the severity of back pain-specific disability with age, body mass index, or smoking status. Conclusions and Relevance: In this cohort of middle-aged, community-dwelling women, there was no evidence to support an association between a higher number of lumbar segments with radiographic changes (K-L grade, osteophytes, and disc space narrowing) and more severe back pain-related disability cross-sectionally or over time. These findings provide further evidence against routinely using diagnostic imaging of the lumbar spine.

The incidence and characteristics of accelerated knee osteoarthritis among women: the Chingford cohort.

BACKGROUND: Prior research on accelerated knee osteoarthritis (AKOA) was primarily confined to the Osteoarthritis Initiative, which was enriched with people with risk factors for knee osteoarthritis (KOA). It is unclear how often AKOA develops in a community-based cohort and whether we can replicate prior findings from the Osteoarthritis Initiative in another cohort. Hence, we determined the incidence and characteristics of AKOA among women in the Chingford Study, which is a prospective community-based cohort. METHODS: The Chingford Study had 1003 women with quinquennial knee radiographs over 15 years. We divided the 15-year observation period into three consecutive 5-year phases. Within each 5-year phase, we selected 3 groups of participants among women who started a phase without KOA (Kellgren-Lawrence [KL] < 2): 1) incident AKOA developed KL grade ≥ 3, 2) typical KOA increased radiographic scoring (excluding AKOA), and 3) no KOA had the same KL grade over time. Study staff recorded each participant's age, body mass index (BMI), and blood pressure at baseline, 5-year, and 10-year study visits. We used multinomial logistic regression models to test the association between groups (outcome) and age, BMI, and blood pressure at the start of each phase. The cumulative incidences and odds ratios (OR) from each phase were pooled using a fixed-effect meta-analysis model. RESULTS: The person-based cumulative incidence of AKOA was 3.9% over 5 years (pooled estimate across the three 5-year phases). Among incident cases of KOA, AKOA represented ~ 15% of women with incident KOA. Women with AKOA were older than those with typical (OR = 1.56, 95%CI = 1.16-2.11) or no KOA (OR = 1.84, 95%CI = 1.40-2.43). Women with AKOA had a greater BMI than those without KOA (OR = 1.52, 95%CI = 1.17-1.97). We observed no association between group and blood pressure. CONCLUSIONS: In a community-based cohort, > 1 in 7 women with incident KOA had AKOA. Like the Osteoarthritis Initiative, people with AKOA were more likely to have greater age and BMI.

TwinsUK: The UK Adult Twin Registry Update.

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. METHODS: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. RESULTS: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10-10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10-9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10-15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10-16). CONCLUSIONS: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Aging Trajectories in Different Body Systems Share Common Environmental Etiology: The Healthy Aging Twin Study (HATS).

Little is known about the extent to which aging trajectories of different body systems share common sources of variance. We here present a large twin study investigating the trajectories of change in five systems: cardiovascular, respiratory, skeletal, morphometric, and metabolic. Longitudinal clinical data were collected on 3,508 female twins in the TwinsUK registry (complete pairs:740 monozygotic (MZ), 986 dizygotic (DZ), mean age at entry 48.9 ± 10.4, range 18-75 years; mean follow-up 10.2 ± 2.8 years, range 4-17.8 years). Panel data on multiple age-related variables were used to estimate biological ages for each individual at each time point, in linear mixed effects models. A weighted average approach was used to combine variables within predefined body system groups. Aging trajectories for each system in each individual were then constructed using linear modeling. Multivariate structural equation modeling of these aging trajectories showed low genetic effects (heritability), ranging from 2% in metabolic aging to 22% in cardiovascular aging. However, we found a significant effect of shared environmental factors on the variations in aging trajectories in cardiovascular (54%), skeletal (34%), morphometric (53%), and metabolic systems (53%). The remainder was due to environmental factors unique to each individual plus error. Multivariate Cholesky decomposition showed that among aging trajectories for various body systems there were significant and substantial correlations between the unique environmental latent factors as well as shared environmental factors. However, there was no evidence for a single common factor for aging. This study, the first of its kind in aging, suggests that diverse organ systems share non-genetic sources of variance for aging trajectories. Confirmatory studies are needed using population-based twin cohorts and alternative methods of handling missing data.

Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.

BACKGROUND: Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II). METHODS: Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage. RESULTS: Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage. CONCLUSIONS: We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.

Association of interleukin-6 gene polymorphisms with hand osteoarthritis and hand osteoporosis.

OBJECTIVE: Several genes, including IL-6 encoding pro-inflammatory cytokines, are involved in development of osteoarthritis and osteoporosis. The association of radiographic hand osteoarthritis (RHOA) and osteoporosis related phenotypes (RHOP) with polymorphisms in IL-6 has been reported inconsistently. The aim of this study was to examine the association, between RHOA and RHOP and IL-6 polymorphisms in two independent samples. METHODS: Two samples: UK females, including 1440 individuals assessed for RHOA and 3470 assessed for RHOP; Chuvash pedigree including 1499 females and males were assessed for RHOP and RHOA. SNPs were genotyped in the IL-6 genomic region, and used in association analysis with RHOA and RHOP phenotypes. RESULTS: RHOP phenotypes showed similar heritability estimates in both samples, ranging from 34.5 ± 5.5% to 61.0 ± 2.4%. RHOA in Chuvash had substantially lower heritability estimates compared to twins (e.g. OSP scores: 11.8 ± 2.3% vs. 39.2 ± 4.1%) with much higher prevalence and considerably stronger correlation with age (r = 0.811 vs. r = 0.505). RHOA in Chuvash sample may be traumatic in nature, caused by heavy and prolonged manual work related to their private farming. There were a number of statistically significant association results with both types of phenotypes. The most consistent result was obtained for JSN in both samples with SNP from the same haploblock. Their combined probability of no association was only p = 0.000003. Additionally, there were SNPs common for both RHOA and RHOP. CONCLUSIONS: We have shown polymorphisms in IL_6 are significantly associated with RHOA and hand RHOP in two samples having different ethnicity and lifestyle. Age × environment × genes interaction appears as an important factor of RHOA manifestation and progression.

Osteophytes, enthesophytes, and high bone mass: a bone-forming triad with potential relevance in osteoarthritis.

OBJECTIVE: Previous studies of skeletal remains have suggested that both enthesophytes and osteophytes are manifestations of an underlying bone-forming tendency. A greater prevalence of osteophytes has been observed among individuals with high bone mass (HBM) compared with controls. This study was undertaken to examine the possible interrelationships between bone mass, enthesophytes, and osteophytes in a population of individuals with extreme HBM. METHODS: Cases of HBM (defined according to bone mineral density [BMD] Z scores on dual x-ray absorptiometry) from the UK-based HBM study were compared with a control group comprising unaffected family members and general population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs from cases and controls were pooled and evaluated, in a blinded manner, by a single observer, who performed semiquantitative grading of the radiographs for the presence and severity of osteophytes and enthesophytes (score range 0-3 for each). Logistic regression analysis was used to identify significant associations, with a priori adjustment for age, sex, and body mass index. RESULTS: In this study, 226 radiographs from HBM cases and 437 radiographs from control subjects were included. Enthesophytes (grade ≥1) and moderate enthesophytes (grade ≥2) were more prevalent in HBM cases compared with controls (adjusted odds ratio [OR] 3.00 [95% confidence interval (95% CI) 1.96-4.58], P < 0.001 for any enthesophyte; adjusted OR 4.33 [95% CI 2.67-7.02], P < 0.001 for moderate enthesophytes). In the combined population of cases and controls, the enthesophyte grade was positively associated with BMD at both the total hip and lumbar spine (adjusted P for trend < 0.001). In addition, a positive association between osteophytes and enthesophytes was observed; for each unit increase in enthesophyte grade, the odds of any osteophyte being present were increased >2-fold (P < 0.001). CONCLUSION: Strong interrelationships were observed between osteophytes, enthesophytes, and HBM, which may be helpful in defining a distinct subset of patients with osteoarthritis characterized by excess bone formation.

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a Mendelian randomisation study.

OBJECTIVE: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information. METHODS: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA. RESULTS: In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA. CONCLUSIONS: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

The UK Adult Twin Registry (TwinsUK Resource).

TwinsUK is a nation-wide registry of volunteer twins in the United Kingdom, with about 12,000 registered twins (83% female, equal number of monozygotic and dizygotic twins, predominantly middle-aged and older). Over the last 20 years, questionnaire and blood/urine/tissue samples have been collected on over 7,000 subjects, as well as three comprehensive phenotyping assessments in the clinical facilities of the Department of Twin Research and Genetic Epidemiology, King's College London. The primary focus of study has been the genetic basis of healthy aging process and complex diseases, including cardiovascular, metabolic, musculoskeletal, and ophthalmologic disorders. Alongside the detailed clinical, biochemical, behavioral, and socio-economic characterization of the study population, the major strength of TwinsUK is availability of several 'omics' technologies for the participants. These include genome-wide scans of single nucleotide variants, next-generation sequencing, exome sequencing, epigenetic markers (MeDIP sequencing), gene expression arrays and RNA sequencing, telomere length measures, metabolomic profiles, and gut flora microbiomics. The scientific community now can freely access parts of the phenotype data from the 'TwinsUK', and interested researchers are encouraged to contact us via our Web site (www.twinsuk.ac.uk) for future collaborations.

Lower limbs composition and radiographic knee osteoarthritis (RKOA) in Chingford sample--a longitudinal study.

Our aim in this longitudinal study was to evaluate to what extent fat and lean tissue mass variations are associated and can predict RKOA in a large sample of British women followed-up over 10 years. Kellgren/Lawrence (K/L), joint space narrowing (JSN) and osteophyte (OSP) grades were scored from radiographs of both knees in 909 middle-aged women from the Chingford registry. Body composition components were assessed using the dual energy X-ray absorptiometry (DXA) method. In cross-sectional analysis, combined effect of age, BMI and leg tissue composition was required for best fitting model explaining variations of K/L scoring and osteophytes at lateral compartment. To explain medial osteophytes, age and BMI were sufficient to generate the best fitting model. In prediction analysis, leg lean mass was the more powerful predictor of K/L, medial osteophytes than BMI. In conclusion, BMI appears to influence the development of knee OA through both fat and/or lean mass, depending on RKOA phenotype.

Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.

Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

Effects of age on genetic influence on bone loss over 17 years in women: the Healthy Ageing Twin Study (HATS).

The rate of bone loss varies across the aging period via multiple complex mechanisms. Therefore, the role of genetic factors on bone loss may also change similarly. In this study, we investigated the effect of age on the genetic component of bone loss in a large twin-based longitudinal study. During 17 years of follow-up in TwinsUK and Healthy Ageing Twin Study (HATS), 15,491 hip and lumbar spine dual-energy X-ray absorptiometry (DXA) scans were performed in 7056 twins. Out of these subjects, 2716 female twins aged >35 years with at least two scans separated for >4 years (mean follow-up 9.7 years) were included in this analysis. We used a mixed-effects random-coefficients regression model to predict hip and spine bone mineral density (BMD) values for exact ages of 40, 45, 50, 55, 60, 65, 70, 75, and 80 years, with adjustment for baseline age, weight, height, and duration of hormone replacement therapy. We then estimated heritability of the changes in BMD measures between these age ranges. Heritability estimates for cross-sectional hip and spine BMD were high (ranging between 69% and 88%) at different ages. Heritability of change of BMD was lower and more variable, generally ranging from 0% to 40% for hip and 0% to 70% for spine; between age 40 and 45 years genetic factors explained 39.9% (95% confidence interval [CI], 25%-53%) of variance of BMD loss for total hip, 46.4% (95% CI, 32%-58%) for femoral neck, and 69.5% (95% CI, 59%-77%) for lumbar spine. These estimates decreased with increasing age, and there appeared to be no heritability of BMD changes after the age of 65 years. There was some evidence at the spine for shared genetic effects between cross-sectional and longitudinal BMD. Whereas genetic factors appear to have an important role in bone loss in early postmenopausal women, nongenetic mechanisms become more important determinants of bone loss with advanced age.