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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/17860

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
Citation: 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.
URI: http://hdl.handle.net/1942/17860
DOI: 10.1136/annrheumdis-2013-204050
ISI #: 000343308200029
ISSN: 0003-4967
Category: A1
Type: Journal Contribution
Validation: ecoom, 2016
Appears in Collections: Research publications

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