title: Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.
abstract: 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.
authors: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
authors: Yolande F M
authors: YF
authors: Ramos
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors: Sarah
authors: S
authors: Metrustry
authors: NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK Arthritis Research UK, Sport, Exercise and Osteoarthritis Centre of Excellence, London, UK.
authors: Nigel
authors: N
authors: Arden
authors: Department of Rheumatology, Nordic Bioscience, Herlev, Denmark.
authors: Anne C
authors: AC
authors: Bay-Jensen
authors: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
authors: Marian
authors: M
authors: Beekman
authors: Department of Gerontology and Geriatrics, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
authors: Anton J M
authors: AJ
authors: de Craen
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA The Framingham Heart Study, Framingham, Massachusetts, USA.
authors: L Adrienne
authors: LA
authors: Cupples
authors: Institute of Molecular and Cell Biology and Estonian Genome Center, University of Tartu, Tartu, Estonia Department of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA Broad Institute, Cambridge, Massachusetts, USA.
authors: Tõnu
authors: T
authors: Esko
authors: Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors: Evangelos
authors: E
authors: Evangelou
authors: Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: David T
authors: DT
authors: Felson
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors: Deborah J
authors: DJ
authors: Hart
authors: Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece Department of Medicine, Stanford Prevention Research Center, Stanford, USA Department of Health Research and Policy, Stanford University School of Medicine, Stanford, USA Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, USA.
authors: John P A
authors: JP
authors: Ioannidis
authors: Department of Rheumatology, Nordic Bioscience, Herlev, Denmark.
authors: Morten
authors: M
authors: Karsdal
authors: Department of Rheumatology & Clinical Epidemiology, LUMC, Leiden, The Netherlands.
authors: Margreet
authors: M
authors: Kloppenburg
authors: Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors: Floris
authors: F
authors: Lafeber
authors: Institute of Molecular and Cell Biology and Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Kalliope
authors: K
authors: Panoutsopoulou
authors: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
authors: P Eline
authors: PE
authors: Slagboom
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors: Tim D
authors: TD
authors: Spector
authors: Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors: Erwin W E
authors: EW
authors: van Spil
authors: The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Global Analytical Science, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA.
authors: Yanyan
authors: Y
authors: Zhu
authors: Academic Rheumatology, University of Nottingham, Nottingham, UK.
authors: Ana M
authors: AM
authors: Valdes
authors: The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Joyce B J
authors: JB
authors: van Meurs
authors: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
authors: Ingrid
authors: I
authors: Meulenbelt
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D064236:Cartilage Oligomeric Matrix Protein / Q000097:blood*; D024043:Collagen Type II / Q000652:urine*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000652:urine*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; C000590554:C-terminal cross-linking telopeptide of type II collagen, human; C477880:CSMD1 protein, human; C573543:MRC1 protein, human; C577553:TSP5 protein, human
keywords: Genetic epidemiology; Genome-wide; Osteoarthritis