Article Text

Extended report
Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis
  1. Rachel Knevel1,
  2. Kerstin Klein2,
  3. Klaartje Somers3,
  4. Caroline Ospelt2,
  5. Jeanine J Houwing-Duistermaat4,
  6. Jessica A B van Nies1,
  7. Diederik P C de Rooy1,
  8. Laura de Bock3,
  9. Fina A S Kurreeman1,5,
  10. Joris Schonkeren1,
  11. Gerrie Stoeken-Rijsbergen1,
  12. Quinta Helmer4,
  13. Michael P M van der Linden1,
  14. Marlena Kern6,
  15. Nataly Manjarrez-Orduno6,
  16. Luis Rodriguez-Rodriquez6,
  17. Piet Stinissen3,
  18. Tom W J Huizinga1,
  19. Rene E M Toes1,
  20. Steffen Gay2,
  21. Peter K Gregersen6,
  22. Veerle Somers3,
  23. Annette H M van der Helm-van Mil1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland
  3. 3Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium
  4. 4Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Feinstein Institute for Medical Research and North Shore–Long Island Jewish Health System, Manhasset, New York, USA
  1. Correspondence to Dr Annette H M van der Helm-van Mil, Department of Rheumatology, C1-R, Leiden University Medical Center Leiden, Leiden 2300 RC, The Netherlands; AvdHelm{at}


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.

  • Rheumatoid Arthritis
  • Gene Polymorphism
  • Outcomes Research

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