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|Title: ||Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis|
|Authors: ||Knevel, Rachel|
van Nies, Jessica A. B.
de Rooy, Diederik P. C.
DE BOCK, Laura
Kurreeman, Fina A. S.
van der Linden, Michael P. M.
Huizinga, Tom W. J.
Toes, Rene E. M.
Gregersen, Peter K.
van der Helm-van Mil, Annette H. M.
|Issue Date: ||2014|
|Publisher: ||BMJ PUBLISHING GROUP|
|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.|
|ISI #: ||000343308200029|
|Type: ||Journal Contribution|
|Validation: ||ecoom, 2016|
|Appears in Collections: ||Research publications|
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