title: Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis.
abstract: BACKGROUND
  Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood.
  
  
  METHODS
  We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo.
  
  
  RESULTS
  A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10(-4)), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion.
  
  
  CONCLUSIONS
  Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rachel
authors: R
authors: Knevel
authors: Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Kerstin
authors: K
authors: Klein
authors: Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium.
authors: Klaartje
authors: K
authors: Somers
authors: Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Caroline
authors: C
authors: Ospelt
authors: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Jeanine J
authors: JJ
authors: Houwing-Duistermaat
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Jessica A B
authors: JA
authors: van Nies
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Diederik P C
authors: DP
authors: de Rooy
authors: Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium.
authors: Laura
authors: L
authors: de Bock
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Fina A S
authors: FA
authors: Kurreeman
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Joris
authors: J
authors: Schonkeren
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Gerrie
authors: G
authors: Stoeken-Rijsbergen
authors: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Quinta
authors: Q
authors: Helmer
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Michael P M
authors: MP
authors: van der Linden
authors: Feinstein Institute for Medical Research and North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors: Marlena
authors: M
authors: Kern
authors: Feinstein Institute for Medical Research and North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors: Nataly
authors: N
authors: Manjarrez-Orduno
authors: Feinstein Institute for Medical Research and North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors: Luis
authors: L
authors: Rodriguez-Rodriquez
authors: Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium.
authors: Piet
authors: P
authors: Stinissen
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Tom W J
authors: TW
authors: Huizinga
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rene E M
authors: RE
authors: Toes
authors: Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Steffen
authors: S
authors: Gay
authors: Feinstein Institute for Medical Research and North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors: Peter K
authors: PK
authors: Gregersen
authors: Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium.
authors: Veerle
authors: V
authors: Somers
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Annette H M
authors: AH
authors: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000097:blood; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D008869:Microtubule-Associated Proteins; C450619:SPAG16 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Gene Polymorphism; Outcomes Research; Rheumatoid Arthritis
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