Please use this identifier to cite or link to this item:
Title: Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis
Authors: Knevel, Rachel
Klein, Kerstin
SOMERS, Klaartje 
Ospelt, Caroline
van Nies, Jessica A. B.
de Rooy, Diederik P. C.
DE BOCK, Laura 
Kurreeman, Fina A. S.
Schonkeren, Joris
Stoeken-Rijsbergen, Gerrie
Helmer, Quinta
van der Linden, Michael P. M.
Kern, Marlena
Manjarrez-Orduno, Nataly
Rodriguez-Rodriquez, Luis
Huizinga, Tom W. J.
Toes, Rene E. M.
Gay, Steffen
Gregersen, Peter K.
SOMERS, Veerle 
van der Helm-van Mil, Annette H. M.
Issue Date: 2014
Source: ANNALS OF THE RHEUMATIC DISEASES, 73 (11), p. 2038-2046
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=1.60x10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28x10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77x10(-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.
Notes: [Knevel, Rachel; van Nies, Jessica A. B.; de Rooy, Diederik P. C.; Kurreeman, Fina A. S.; Schonkeren, Joris; Stoeken-Rijsbergen, Gerrie; van der Linden, Michael P. M.; Huizinga, Tom W. J.; Toes, Rene E. M.; van der Helm-van Mil, Annette H. M.] Leiden Univ, Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands. [Klein, Kerstin; Ospelt, Caroline; Gay, Steffen] Univ Zurich Hosp, Ctr Expt Rheumatol, CH-8091 Zurich, Switzerland. [Klein, Kerstin; Ospelt, Caroline; Gay, Steffen] Zurich Ctr Integrat Human Physiol ZIHP, Zurich, Switzerland. [Somers, Klaartje; de Bock, Laura; Stinissen, Piet; Somers, Veerle] Hasselt Univ, Biomed Res Inst, Diepenbeek, Belgium. [Houwing-Duistermaat, Jeanine J.; Helmer, Quinta] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands. [Kurreeman, Fina A. S.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Kern, Marlena; Manjarrez-Orduno, Nataly; Rodriguez-Rodriquez, Luis; Gregersen, Peter K.] Feinstein Inst Med Res, Manhasset, NY USA. [Kern, Marlena; Manjarrez-Orduno, Nataly; Rodriguez-Rodriquez, Luis; Gregersen, Peter K.] North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA.
Document URI:
ISSN: 0003-4967
e-ISSN: 1468-2060
DOI: 10.1136/annrheumdis-2013-204050
ISI #: 000343308200029
Category: A1
Type: Journal Contribution
Validations: ecoom 2016
Appears in Collections:Research publications

Files in This Item:
File Description SizeFormat 
Identiļ¬cation of a genetic variant for joint_SPAG16+RA.pdf
  Restricted Access
1.11 MBAdobe PDFView/Open    Request a copy
Show full item record


checked on Sep 5, 2020


checked on May 21, 2022

Page view(s)

checked on May 25, 2022


checked on May 25, 2022

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.