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1.  Hand-related physical function in rheumatic hand conditions: a protocol for developing a patient-reported outcome measurement instrument 
BMJ Open  2016;6(12):e011174.
Introduction
There is no consensus about what constitutes the most appropriate patient-reported outcome measurement (PROM) instrument for measuring physical function in patients with rheumatic hand conditions. Existing instruments lack psychometric testing and vary in feasibility and their psychometric qualities. We aim to develop a PROM instrument to assess hand-related physical function in rheumatic hand conditions.
Methods and analysis
We will perform a systematic search to identify existing PROMs to rheumatic hand conditions, and select items relevant for hand-related physical function as well as those items from the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) item bank that are relevant to patients with rheumatic hand conditions. Selection will be based on consensus among reviewers. Content validity of selected items will be established through the use of focus groups. If patients deem necessary, we will develop new items based on the patients' input. We will examine whether it is valid to score all selected and developed items on the same scale as the original items from the PROMIS PF item bank. Our analyses will follow the methods used for calibrating the original PROMIS PF item bank in US samples, which were largely based on the general PROMIS approach.
Ethics and dissemination
This study will be carried out in accordance with the Helsinki Declaration. Ethics approvals will be obtained where necessary, and signed informed consent will be obtained from all participants. We aim to disseminate the results of the study through publication in international peer-reviewed journals and at international conferences.
doi:10.1136/bmjopen-2016-011174
PMCID: PMC5168653  PMID: 27974367
Hand function; Arthritis; Outcome Measurement Instrument; PROMIS
2.  Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis 
PLoS Genetics  2016;12(10):e1006260.
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.
Author Summary
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability in the western society affecting millions of people. OA is a degenerative joint disease characterized by changes in all joint tissues, including cartilage, bone and synovium, causing chronic pain and loss of function. There are no effective therapeutic treatments available for OA and therefore finding novel biological pathways through genetic association studies can open up new treatment options. The number of known DNA variants associated with OA-risk is limited.
To identify new loci, we have performed a Genome Wide Association Study meta-analysis on cartilage thickness, one of the joint tissues affected in OA in a total sample of more than 20,000 individuals from twelve cohorts. This analysis revealed six variants associated with cartilage thickness, four of these being novel associations, including TGFA as the most prominent one. A systematic prioritization for underlying causal genes, using diverse lines of evidence, highlighted genes underlying the disease associations, including TGFA, RUNX2 and PIK3R1. Large scale exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies
doi:10.1371/journal.pgen.1006260
PMCID: PMC5049763  PMID: 27701424
3.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
4.  Associations between joint effusion in the knee and gene expression levels in the circulation: a meta-analysis 
F1000Research  2016;5:109.
Objective: To identify molecular biomarkers for early knee osteoarthritis (OA), we examined whether joint effusion in the knee associated with different gene expression levels in the circulation.
Materials and Methods: Joint effusion grades measured with magnetic resonance (MR) imaging and gene expression levels in blood were determined in women of the Rotterdam Study (N=135) and GARP (N=98). Associations were examined using linear regression analyses, adjusted for age, fasting status, RNA quality, technical batch effects, blood cell counts, and BMI. To investigate enriched pathways and protein-protein interactions, we used the DAVID and STRING webtools.
Results: In a meta-analysis, we identified 257 probes mapping to 189 unique genes in blood that were nominally significantly associated with joint effusion grades in the knee. Several compelling genes were identified such as C1orf38 and NFATC1. Significantly enriched biological pathways were: response to stress, gene expression, negative regulation of intracellular signal transduction, and antigen processing and presentation of exogenous pathways.
Conclusion: Meta-analyses and subsequent enriched biological pathways resulted in interesting candidate genes associated with joint effusion that require further characterization. Associations were not transcriptome-wide significant most likely due to limited power. Additional studies are required to replicate our findings in more samples, which will greatly help in understanding the pathophysiology of OA and its relation to inflammation, and may result in biomarkers urgently needed to diagnose OA at an early stage.
doi:10.12688/f1000research.7763.1
PMCID: PMC4837985  PMID: 27134727
knee osteoarthritis; joint effusion; molecular markers; inflammation; blood
5.  Intra-Articular Therapies in the Treatment of Hand Osteoarthritis: A Systematic Literature Review 
Drugs & Aging  2015;33:119-133.
Background
Local treatments to alleviate symptoms in hand osteoarthritis (OA) are preferred, especially in elderly patients with comorbidities. Therefore, we have summarized the benefits and harms of intra-articular (IA) therapies.
Methods
We conducted a systematic literature review until May 2015, including all controlled trials investigating efficacy or safety of any IA therapy in carpometacarpal (CMC) and interphalangeal (IP) OA compared with placebo or other treatments. Two authors independently selected trials and assessed risk of bias using the Cochrane tool. The main efficacy outcome was pain. We performed meta-analysis where appropriate.
Results
A total of 13 trials (864 patients) studying CMC (n = 11) and IP OA (n = 2) were included, comparing corticosteroids or hyaluronic acid (HA) versus placebo (n = 4 and n = 3), and corticosteroids versus HA (n = 6). Single studies investigated infliximab, dextrose, and different HAs. The overall risk of bias was unclear or high in most trials. Meta-analysis of two trials comparing corticosteroids with placebo in CMC OA showed no improvement in pain [mean difference −3.56, 95 % confidence interval (CI) −13.87 to 6.75, scale 0–100). HA also appeared not efficacious compared with placebo in CMC OA. One trial comparing corticosteroids with placebo in IP OA demonstrated significantly improved pain during movement. No convincing evidence for efficacy of corticosteroids or HA over the other or alternative therapies was found. Only local adverse events were reported. No specific IA therapy appeared more harmful than another.
Conclusion
Despite a beneficial short-term safety profile, IA corticosteroids or HA do not appear more effective than placebo in CMC OA. The suggestion that IA corticosteroids might be efficacious in IP OA requires confirmation.
Electronic supplementary material
The online version of this article (doi:10.1007/s40266-015-0330-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s40266-015-0330-5
PMCID: PMC4756050  PMID: 26650235
6.  Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies 
Objective
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.
Methods
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.
Results
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Conclusion
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
doi:10.1002/art.38300
PMCID: PMC4660891  PMID: 24757145
7.  The transcriptional landscape of age in human peripheral blood 
Peters, Marjolein J. | Joehanes, Roby | Pilling, Luke C. | Schurmann, Claudia | Conneely, Karen N. | Powell, Joseph | Reinmaa, Eva | Sutphin, George L. | Zhernakova, Alexandra | Schramm, Katharina | Wilson, Yana A. | Kobes, Sayuko | Tukiainen, Taru | Ramos, Yolande F. | Göring, Harald H. H. | Fornage, Myriam | Liu, Yongmei | Gharib, Sina A. | Stranger, Barbara E. | De Jager, Philip L. | Aviv, Abraham | Levy, Daniel | Murabito, Joanne M. | Munson, Peter J. | Huan, Tianxiao | Hofman, Albert | Uitterlinden, André G. | Rivadeneira, Fernando | van Rooij, Jeroen | Stolk, Lisette | Broer, Linda | Verbiest, Michael M. P. J. | Jhamai, Mila | Arp, Pascal | Metspalu, Andres | Tserel, Liina | Milani, Lili | Samani, Nilesh J. | Peterson, Pärt | Kasela, Silva | Codd, Veryan | Peters, Annette | Ward-Caviness, Cavin K. | Herder, Christian | Waldenberger, Melanie | Roden, Michael | Singmann, Paula | Zeilinger, Sonja | Illig, Thomas | Homuth, Georg | Grabe, Hans-Jörgen | Völzke, Henry | Steil, Leif | Kocher, Thomas | Murray, Anna | Melzer, David | Yaghootkar, Hanieh | Bandinelli, Stefania | Moses, Eric K. | Kent, Jack W. | Curran, Joanne E. | Johnson, Matthew P. | Williams-Blangero, Sarah | Westra, Harm-Jan | McRae, Allan F. | Smith, Jennifer A. | Kardia, Sharon L. R. | Hovatta, Iiris | Perola, Markus | Ripatti, Samuli | Salomaa, Veikko | Henders, Anjali K. | Martin, Nicholas G. | Smith, Alicia K. | Mehta, Divya | Binder, Elisabeth B. | Nylocks, K Maria | Kennedy, Elizabeth M. | Klengel, Torsten | Ding, Jingzhong | Suchy-Dicey, Astrid M. | Enquobahrie, Daniel A. | Brody, Jennifer | Rotter, Jerome I. | Chen, Yii-Der I. | Houwing-Duistermaat, Jeanine | Kloppenburg, Margreet | Slagboom, P. Eline | Helmer, Quinta | den Hollander, Wouter | Bean, Shannon | Raj, Towfique | Bakhshi, Noman | Wang, Qiao Ping | Oyston, Lisa J. | Psaty, Bruce M. | Tracy, Russell P. | Montgomery, Grant W. | Turner, Stephen T. | Blangero, John | Meulenbelt, Ingrid | Ressler, Kerry J. | Yang, Jian | Franke, Lude | Kettunen, Johannes | Visscher, Peter M. | Neely, G. Gregory | Korstanje, Ron | Hanson, Robert L. | Prokisch, Holger | Ferrucci, Luigi | Esko, Tonu | Teumer, Alexander | van Meurs, Joyce B. J. | Johnson, Andrew D.
Nature Communications  2015;6:8570.
Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.
doi:10.1038/ncomms9570
PMCID: PMC4639797  PMID: 26490707
8.  Prevalence of cartilaginous tumours as an incidental finding on MRI of the knee 
European Radiology  2015;25(12):3480-3487.
Objectives
The purpose was to determine prevalence of enchondromas and atypical cartilaginous tumour/chondrosarcoma grade 1 (ACT/CS1) of the knee on MRI in a large cohort study, namely the Netherlands Epidemiology of Obesity (NEO) study.
Methods
Participants aged 45 to 65 years were prospectively included, oversampling overweight and obese persons. Within a subgroup of participants, MRI of the right knee was performed and screened for incidental cartilaginous tumours, as defined by their characteristic location and appearance.
Results
Forty-nine cartilaginous tumours were observed in 44 out of 1285 participants (estimated population prevalence 2.8 %, 95 % CI 2.0–4.0 %). Mean largest tumour diameter was 12 mm (range 2–31 mm). Eight participants with a tumour larger than 20 mm or a tumour with aggressive features were referred to rule out low-grade chondrosarcoma. One was lost to follow-up, three had histologically proven ACT/CS1 and four had dynamic contrast MRI findings consistent with benign enchondroma.
Conclusions
Incidental cartilaginous tumours were relatively common on knee MRI and may be regarded as a normal concurrent finding. However, more tumours than expected were ACT/CS1. Because further examination was performed only when suspicion of chondrosarcoma was high, the actual prevalence might be even higher.
Key Points
• Incidental cartilaginous tumours are relatively common on knee MRI.
• Most incidental cartilaginous tumours are small and lack suspicious features.
• Small cartilaginous tumours without suspicious findings may be a normal concurrent finding.
• Large tumours and/or those with suspicious findings should be further investigated.
• Atypical cartilaginous tumour/chondrosarcoma grade 1 was found more often than expected.
doi:10.1007/s00330-015-3764-6
PMCID: PMC4636526  PMID: 25994192
Magnetic resonance imaging; Chondroma; Chondrosarcoma; Knee; Incidental findings
9.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
doi:10.1002/art.24524
PMCID: PMC4412885  PMID: 19479880
10.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
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.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
11.  Updating the OMERACT Filter: Implications for imaging and soluble biomarkers 
The Journal of rheumatology  2014;41(5):1016-1024.
Objective
The OMERACT Filter provides a framework for the validation of outcome measures for use in rheumatology clinical research. However, imaging and biochemical measures may face additional validation challenges due to their technical nature. The Imaging and Soluble Biomarker Session at OMERACT 11 aimed to provide a guide for the iterative development of an imaging or biochemical measurement instrument so it can be used in therapeutic assessment.
Methods
A hierarchical structure was proposed, reflecting 3 dimensions needed for validating an imaging or biochemical measurement instrument: outcome domain(s), study setting and performance of the instrument. Movement along the axes in any dimension reflects increasing validation. For a given test instrument, the 3-axis structure assesses the extent to which the instrument is a validated measure for the chosen domain, whether it assesses a patient or disease centred-variable, and whether its technical performance is adequate in the context of its application. Some currently used imaging and soluble biomarkers for rheumatoid arthritis, spondyloarthritis and knee osteoarthritis were then evaluated using the original OMERACT filter and the newly proposed structure. Break-out groups critically reviewed the extent to which the candidate biomarkers complied with the proposed step-wise approach, as a way of examining the utility of the proposed 3 dimensional structure.
Results
Although there was a broad acceptance of the value of the proposed structure in general, some areas for improvement were suggested including clarification of criteria for achieving a certain level of validation and how to deal with extension of the structure to areas beyond clinical trials.
Conclusion
General support was obtained for a proposed tri-axis structure to assess validation of imaging and soluble biomarkers; nevertheless, additional work is required to better evaluate its place within the OMERACT Filter 2.0.
doi:10.3899/jrheum.131313
PMCID: PMC4223089  PMID: 24584916
biomarkers; imaging; OMERACT filter; validation framework
12.  Updating the OMERACT Filter: Core Areas as a basis for defining core outcome sets 
The Journal of rheumatology  2014;41(5):994-999.
Objective
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter pre-supposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement (“Filter 2.0 Core Areas of Measurement”) was presented at OMERACT 11 to explore areas of consensus and consider whether already endorsed core outcome sets fit in to this newly proposed framework.
Method
Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved.
Result
Although there was a broad acceptance of the framework in general, several important areas of construction, presentation and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues.
Conclusion
These issues will require resolution in order to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.
doi:10.3899/jrheum.131309
PMCID: PMC4217644  PMID: 24634204
13.  The role of pain and functional impairment in the decision to recommend total joint replacement in hip and knee osteoarthritis: an international cross-sectional study of 1909 patients. Report of the OARSI-OMERACT Task Force on total joint replacement 
Objective
To assess the pain and functional disability levels corresponding to an indication for total joint replacement (TJR) in hip and knee osteoarthritis (OA).
Methods
Design: international cross-sectional study in 10 countries. Patients: consecutive outpatients with definite hip or knee OA attending an orthopaedic outpatient clinic. Gold standard measure for recommendation for TJR: surgeon's decision that TJR is justified. Outcome measures: pain (ICOAP: intermittent and constant osteoarthritis pain, 0-100) and functional impairment (HOOS-PS/KOOS-PS: Hip/Knee injury and Osteoarthritis Outcome Score Physical function Short-form, 0-100). Analyses: Comparison of patients with versus without surgeons' indication for TJR. ROC curve analyses and logistic regression were applied to determine cut-points of pain and disability defining recommendation for TJR.
Results
In all, 1909 patients were included (1130 knee/779 hip OA). Mean age was 66.4 (SD 10.9) years, 58.1% were women; 628/1130 (55.6%) knee OA and 574/779 (73.7%) hip OA patients were recommended for TJR. Although patients recommended for TJR (yes versus no) had worse symptom levels (pain, 55.5 [95% confidence interval 54.2, 56.8] vs. 44.9 [43.2, 46.6], and functional impairment, 59.8 [58.7, 60.9] vs. 50.9 [49.3, 52.4], respectively, both p<0.0001), there was substantial overlap in symptom levels between groups, even when adjusting for radiographic joint status. Thus, it was not possible to determine cut points for pain and function defining ‘requirement for TJR’.
Conclusion
Although symptom levels were higher in patients recommended for TJR, pain and functional disability alone did not discriminate between those who were and were not considered to need TJR by the orthopaedic surgeon.
doi:10.1016/j.joca.2010.10.025
PMCID: PMC4151518  PMID: 21044689
Knee; hip; osteoarthritis; joint replacement; surgery; symptom
14.  An emerging player in knee osteoarthritis: the infrapatellar fat pad 
The role of inflammation in the development, progression, and clinical features of osteoarthritis has become an area of intense research in recent years. This led to the recognition of synovitis as an important source of inflammation in the joint and indicated that synovitis is intimately associated with pain and osteoarthritis progression. In this review, we discuss another emerging source of inflammation that could play a role in disease development/progression: the infrapatellar fat pad (IFP). The aim of this review is to offer a comprehensive view of the pathology of IFP as obtained from magnetic resonance studies, along with its characterization at both the cellular and the molecular level. Furthermore, we discuss the possible function of this organ in the pathological processes in the knee by summarizing the knowledge regarding the interactions between IFP and other joint tissues and discussing the pro- versus anti-inflammatory functions this tissue could have. We hope that this review will offer an overview of all published data regarding the IFP and will indicate novel directions for future research.
doi:10.1186/ar4422
PMCID: PMC3979009  PMID: 24367915
15.  The diagnostic performance of MRI in osteoarthritis: a systematic review and meta-analysis 
Objective
Osteoarthritis (OA) is currently diagnosed using clinical and radiographic findings. In recent years MRI use in osteoarthritis has increasingly been studied. This study was conducted to determine the diagnostic utility of MRI in OA through a meta-analysis of published studies.
Methods
A systematic literature search was undertaken to include studies that used MRI to evaluate or detect osteoarthritis. MRI was compared to various reference standards: histology, arthroscopy, radiography, CT, clinical evaluation, and direct visual inspection. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) area under the curve were calculated. Random effects models were used to pool results.
Results
Of 20 relevant studies identified from the literature, 16 reported complete data and were included in the meta-analysis, with a total of 1220 patients (1071 with OA and 149 without). Overall sensitivity from pooling data of all the included studies was 61% (95% confidence interval [CI] 53 to 68), specificity was 82% (95% CI 77 to 87), PPV was 85% (95% CI 80 to 88), and NPV was 57% (95% CI 43 to 70). The ROC showed an area under the curve of 0.804. There was significant heterogeneity in the above parameters (I2 >83%). With histology as the reference standard, sensitivity increased to 74% and specificity decreased to 76% compared with all reference standards combined. When arthroscopy was used as the reference standard, sensitivity increased to 69% and specificity to 93% compared with all reference standards combined.
Conclusion
MRI can detect OA with an overall high specificity and moderate sensitivity when compared with various reference standards, thus lending more utility to ruling out OA than ruling it in. The sensitivity of MRI is below the current clinical diagnostic standards. At this time standard clinical algorithm for OA diagnosis, aided by radiographs appears to be the most effective method for diagnosing OA.
doi:10.1016/j.joca.2011.10.003
PMCID: PMC3934362  PMID: 22044841
Osteoarthritis; diagnosis; MRI
16.  Adiposity and hand osteoarthritis: the Netherlands Epidemiology of Obesity study 
Introduction
Obesity, usually characterized by the body mass index (BMI), is a risk factor for hand osteoarthritis (OA). We investigated whether adipose tissue and abdominal fat distribution are associated with hand OA.
Methods
The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45 to 65 years, including 5315 participants (53% women, median BMI 29.9 kg/m2). Fat percentage and fat mass (FM) (kg) were estimated using bioelectrical impedance analysis. The waist-to-hip ratio (WHR) was calculated. In 1721 participants, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (cm2) were assessed using abdominal MR imaging. Hand OA was defined according to the ACR criteria.
Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of fat percentage, FM, WHR, VAT and SAT with hand OA using logistic regression analyses per standard deviation, stratified by sex and adjusted for age.
Results
Hand OA was present in 8% of men and 20% of women. Fat percentage was associated with hand OA in men (OR 1.34 (95% CI 1.11 to 1.61)) and women (OR 1.26 (1.05 to 1.51)), as was FM. WHR was associated with hand OA in men (OR 1.45 (1.13 to 1.85)), and to a lesser extent in women (OR 1.17 (1.00 to 1.36)). Subgroup analysis revealed that VAT was associated with hand OA in men (OR1.33 (1.01 to 1.75)). This association increased after additional adjustment for FM (OR 1.51 (1.13 to 2.03)).
Conclusions
Fat percentage, FM and WHR were associated with hand OA. VAT was associated with hand OA in men, suggesting involvement of visceral fat in hand OA.
doi:10.1186/ar4447
PMCID: PMC3978723  PMID: 24447395
17.  Fatty Acids, Lipid Mediators, and T-Cell Function 
Research toward the mechanisms underlying obesity-linked complications has intensified during the last years. As a consequence, it has become clear that metabolism and immunity are intimately linked. Free fatty acids and other lipids acquired in excess by current feeding patterns have been proposed to mediate this link due to their immune modulatory capacity. The functional differences between saturated and unsaturated fatty acids, in combination with their dietary intake are believed to modulate the outcome of immune responses. Moreover, unsaturated fatty acids can be oxidized in a tightly regulated and specific manner to generate either potent pro-inflammatory or pro-resolving lipid mediators. These oxidative derivatives of fatty acids have received detailed attention during the last years, as they have proven to have strong immune modulatory capacity, even in pM ranges. Both fatty acids and oxidized fatty acids have been studied especially in relation to macrophage and T-cells functions. In this review, we propose to focus on the effect of fatty acids and their oxidative derivatives on T-cells, as it is an active area of research during the past 5 years. The effect of fatty acids and their derivatives on activation and proliferation of T-cells, as well as the delicate balance between stimulation and lipotoxicity will be discussed. Moreover, the receptors involved in the interaction between free fatty acids and their derivatives with T-cells will be summarized. Finally, the mechanisms involved in modulation of T-cells by fatty acids will be addressed, including cellular signaling and metabolism of T-cells. The in vitro results will be placed in context of in vivo studies both in humans and mice. In this review, we summarize the latest findings on the immune modulatory function of lipids on T-cells and will point out novel directions for future research.
doi:10.3389/fimmu.2014.00483
PMCID: PMC4195378  PMID: 25352844
T-cells; fatty acids; lipid mediators; obesity; inflammation
18.  Comparison of clinical burden between patients with erosive hand osteoarthritis and inflammatory arthritis in symptomatic community-dwelling adults: the Keele clinical assessment studies 
Rheumatology (Oxford, England)  2013;52(12):2260-2267.
Objective. To investigate in the general population the clinical impact of erosive OA in interphalangeal joints (IPJs) compared with symptomatic radiographic hand OA and inflammatory arthritis.
Methods. Standardized assessments with hand radiographs were performed in participants of two population-based cohorts in North Staffordshire with hand symptoms lasting ≥1 day in the past month. Erosive OA was defined as the presence of an eroded or remodelled phase in ≥1 IPJ using the Verbruggen–Veys method. Radiographic hand OA was defined as the presence of ≥1 IPJ/first carpometacarpal joint with a Kellgren–Lawrence score of ≥2. Diagnoses of inflammatory arthritis were based on medical records. Hand pain and disability were assessed with the Australian/Canadian Hand Osteoarthritis Index (AUSCAN). Linear regression analyses were used to compare clinical determinants between groups and calculate mean differences with 95% CIs, adjusted for age and sex.
Results. Of 1076 participants with hand symptoms [60% women, mean age 64.8 years (s.d. 8.3 years)]; 80 persons (7.4%) had erosive OA. The population prevalence of erosive OA in ≥1 IPJ was 2.4% (95% CI 1.8, 3.0). Persons with erosive OA reported more pain and disability than persons with symptomatic radiographic hand OA [adjusted mean difference 1.3 (95% CI 0.3, 2.3) and 2.3 (95% CI 0.4, 4.2), respectively]. Individuals with inflammatory arthritis (n = 44) reported more pain and disability than those with erosive OA [adjusted mean difference 1.7 (95% CI 0.05, 3.4) and 6.3 (95% CI 2.8, 9.9), respectively].
Conclusion. While erosive OA has a greater impact than symptomatic radiographic hand OA in the general population, it is not as severe in terms of hand pain and disability as inflammatory RA.
doi:10.1093/rheumatology/ket267
PMCID: PMC3828511  PMID: 24046470
erosions; hand osteoarthritis; inflammatory arthritis; pain; function
19.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
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 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). 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 CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, 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=1.14-1.32, 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.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
20.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
doi:10.1136/ard.2010.132787
PMCID: PMC3615180  PMID: 21068099
21.  A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function 
Porcu, Eleonora | Medici, Marco | Pistis, Giorgio | Volpato, Claudia B. | Wilson, Scott G. | Cappola, Anne R. | Bos, Steffan D. | Deelen, Joris | den Heijer, Martin | Freathy, Rachel M. | Lahti, Jari | Liu, Chunyu | Lopez, Lorna M. | Nolte, Ilja M. | O'Connell, Jeffrey R. | Tanaka, Toshiko | Trompet, Stella | Arnold, Alice | Bandinelli, Stefania | Beekman, Marian | Böhringer, Stefan | Brown, Suzanne J. | Buckley, Brendan M. | Camaschella, Clara | de Craen, Anton J. M. | Davies, Gail | de Visser, Marieke C. H. | Ford, Ian | Forsen, Tom | Frayling, Timothy M. | Fugazzola, Laura | Gögele, Martin | Hattersley, Andrew T. | Hermus, Ad R. | Hofman, Albert | Houwing-Duistermaat, Jeanine J. | Jensen, Richard A. | Kajantie, Eero | Kloppenburg, Margreet | Lim, Ee M. | Masciullo, Corrado | Mariotti, Stefano | Minelli, Cosetta | Mitchell, Braxton D. | Nagaraja, Ramaiah | Netea-Maier, Romana T. | Palotie, Aarno | Persani, Luca | Piras, Maria G. | Psaty, Bruce M. | Räikkönen, Katri | Richards, J. Brent | Rivadeneira, Fernando | Sala, Cinzia | Sabra, Mona M. | Sattar, Naveed | Shields, Beverley M. | Soranzo, Nicole | Starr, John M. | Stott, David J. | Sweep, Fred C. G. J. | Usala, Gianluca | van der Klauw, Melanie M. | van Heemst, Diana | van Mullem, Alies | H.Vermeulen, Sita | Visser, W. Edward | Walsh, John P. | Westendorp, Rudi G. J. | Widen, Elisabeth | Zhai, Guangju | Cucca, Francesco | Deary, Ian J. | Eriksson, Johan G. | Ferrucci, Luigi | Fox, Caroline S. | Jukema, J. Wouter | Kiemeney, Lambertus A. | Pramstaller, Peter P. | Schlessinger, David | Shuldiner, Alan R. | Slagboom, Eline P. | Uitterlinden, André G. | Vaidya, Bijay | Visser, Theo J. | Wolffenbuttel, Bruce H. R. | Meulenbelt, Ingrid | Rotter, Jerome I. | Spector, Tim D. | Hicks, Andrew A. | Toniolo, Daniela | Sanna, Serena | Peeters, Robin P. | Naitza, Silvia
PLoS Genetics  2013;9(2):e1003266.
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Author Summary
Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.
doi:10.1371/journal.pgen.1003266
PMCID: PMC3567175  PMID: 23408906
22.  OARSI/OMERACT Initiative to Define States of Severity and Indication for Joint Replacement in Hip and Knee Osteoarthritis. An OMERACT 10 Special Interest Group 
The Journal of Rheumatology  2011;38(8):1765-1769.
Objective
To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of “need for joint replacement surgery,” for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA).
Methods
New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons’ indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA.
Results
In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%–12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0–100) + physical function (0–100) > 80].
Conclusion
These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define “nonresponders” to disease-modifying drugs in OA clinical trials.
doi:10.3899/jrheum.110403
PMCID: PMC3260473  PMID: 21807799
OSTEOARTHRITIS; SEVERITY; PAIN; FUNCTION; STRUCTURE OUTCOME MEASURE
23.  A Genome-Wide Association Study identifies a locus on chromosome 7q22 to influence susceptibility for osteoarthritis 
Arthritis and Rheumatism  2010;62(2):499-510.
To identify genes involved in osteoarthritis (OA), the most prevalent form of joint disease, we performed a genome-wide association study (GWAS) in which we tested 500,510 Single Nucelotide Polymorphisms (SNPs) in 1341 OA cases and 3496 Dutch Caucasian controls. SNPs associated with at least two OA-phenotypes were analysed in 14,938 OA cases and approximately 39,000 controls. The C-allele of rs3815148 on chromosome 7q22 (MAF 23%, 172 kb upstream of the GPR22 gene) was consistently associated with a 1.14-fold increased risk (95%CI: 1.09–1.19) for knee- and/or hand-OA (p=8×10−8), and also with a 30% increased risk for knee-OA progression (95%CI: 1.03–1.64, p=0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (located 68 kb upstream of GPR22) which is associated with GPR22 expression levels in lymphoblast cell lines (p=4×10−12). GPR22 encodes an G-protein coupled receptor with unkown ligand (orphan receptor). Immunohistochemistry experiments showed absence of GPR22 in normal mouse articular cartilage or synovium. However, GPR22 positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged by in vivo papain treatment or in the presence of interleukin-1 driven inflammation. GRP22 positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. In addition, GPR22 is also present in areas of the brain involved in locomotor function. Our findings reveal a novel common variant on chromosome 7q22 to influence susceptibility for prevalence and progression of OA.
doi:10.1002/art.27184
PMCID: PMC3354739  PMID: 20112360
24.  Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals 
Dastani, Zari | Hivert, Marie-France | Timpson, Nicholas | Perry, John R. B. | Yuan, Xin | Scott, Robert A. | Henneman, Peter | Heid, Iris M. | Kizer, Jorge R. | Lyytikäinen, Leo-Pekka | Fuchsberger, Christian | Tanaka, Toshiko | Morris, Andrew P. | Small, Kerrin | Isaacs, Aaron | Beekman, Marian | Coassin, Stefan | Lohman, Kurt | Qi, Lu | Kanoni, Stavroula | Pankow, James S. | Uh, Hae-Won | Wu, Ying | Bidulescu, Aurelian | Rasmussen-Torvik, Laura J. | Greenwood, Celia M. T. | Ladouceur, Martin | Grimsby, Jonna | Manning, Alisa K. | Liu, Ching-Ti | Kooner, Jaspal | Mooser, Vincent E. | Vollenweider, Peter | Kapur, Karen A. | Chambers, John | Wareham, Nicholas J. | Langenberg, Claudia | Frants, Rune | Willems-vanDijk, Ko | Oostra, Ben A. | Willems, Sara M. | Lamina, Claudia | Winkler, Thomas W. | Psaty, Bruce M. | Tracy, Russell P. | Brody, Jennifer | Chen, Ida | Viikari, Jorma | Kähönen, Mika | Pramstaller, Peter P. | Evans, David M. | St. Pourcain, Beate | Sattar, Naveed | Wood, Andrew R. | Bandinelli, Stefania | Carlson, Olga D. | Egan, Josephine M. | Böhringer, Stefan | van Heemst, Diana | Kedenko, Lyudmyla | Kristiansson, Kati | Nuotio, Marja-Liisa | Loo, Britt-Marie | Harris, Tamara | Garcia, Melissa | Kanaya, Alka | Haun, Margot | Klopp, Norman | Wichmann, H.-Erich | Deloukas, Panos | Katsareli, Efi | Couper, David J. | Duncan, Bruce B. | Kloppenburg, Margreet | Adair, Linda S. | Borja, Judith B. | Wilson, James G. | Musani, Solomon | Guo, Xiuqing | Johnson, Toby | Semple, Robert | Teslovich, Tanya M. | Allison, Matthew A. | Redline, Susan | Buxbaum, Sarah G. | Mohlke, Karen L. | Meulenbelt, Ingrid | Ballantyne, Christie M. | Dedoussis, George V. | Hu, Frank B. | Liu, Yongmei | Paulweber, Bernhard | Spector, Timothy D. | Slagboom, P. Eline | Ferrucci, Luigi | Jula, Antti | Perola, Markus | Raitakari, Olli | Florez, Jose C. | Salomaa, Veikko | Eriksson, Johan G. | Frayling, Timothy M. | Hicks, Andrew A. | Lehtimäki, Terho | Smith, George Davey | Siscovick, David S. | Kronenberg, Florian | van Duijn, Cornelia | Loos, Ruth J. F. | Waterworth, Dawn M. | Meigs, James B. | Dupuis, Josee | Richards, J. Brent
PLoS Genetics  2012;8(3):e1002607.
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Author Summary
Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.
doi:10.1371/journal.pgen.1002607
PMCID: PMC3315470  PMID: 22479202
25.  The model of erosive hand osteoarthritis 
Arthritis Research & Therapy  2012;14(Suppl 2):A8.
doi:10.1186/ar3715
PMCID: PMC3353576

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