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Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis
  1. Diederik P C de Rooy1,
  2. Nataliya G Yeremenko2,
  3. Anthony Gerard Wilson3,
  4. Rachel Knevel1,
  5. Elisabet Lindqvist4,5,
  6. Tore Saxne4,5,
  7. Annemarie Krabben1,
  8. Martha K Leijsma6,
  9. Nina A Daha1,
  10. S Tsonaka7,
  11. Sasha A Zhernakova1,
  12. J J Houwing-Duistermaat7,
  13. Tom W J Huizinga1,
  14. René E M Toes1,
  15. Dominique L P Baeten2,
  16. E Brouwer6,
  17. Annette H M van der Helm-van Mil1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  3. 3School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK
  4. 4Department of Clinical Sciences, Lund, Section of Rheumatology, Lund University, Lund, Sweden
  5. 5Department of Rheumatology, Skåne University Hospital, Lund, Sweden
  6. 6Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center, Groningen, The Netherlands
  7. 7Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Diederik P C de Rooy, Department of Rheumatology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands; d.p.c.de_rooy{at}lumc.nl

Abstract

Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/β-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway.

Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction.

Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes.

Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene–gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02).

Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.

  • Rheumatoid Arthritis
  • Gene Polymorphism
  • Bone Mineral Density

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  • Correction
    BMJ Publishing Group Ltd and European League Against Rheumatism