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SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis
  1. Pierre-Antoine Juge1,
  2. Hanna W van Steenbergen2,
  3. Arnaud Constantin3,
  4. Gabriel J Tobon4,
  5. Thierry Schaeverbeke5,
  6. Steven Gazal6,
  7. Bernard Combe7,
  8. Valérie Devauchelle-Pensec4,
  9. Delphine Nigon3,
  10. Annette H M van der Helm-van Mil2,
  11. Philippe Dieude1,8
  1. 1Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  2. 2Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3UMR 1027, INSERM, Toulouse III University and Department of Rheumatology, Purpan Hospital, CHU Toulouse, Toulouse, France
  4. 4Department of Rheumatology, Morvan Hospital, Cavale Blanche Hospital, Brittany University, Brest, France
  5. 5Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France
  6. 6Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  7. 7Department of Rheumatology, Montpellier University Hospital, Montpellier, France
  8. 8INSERM U699, Bichat Faculty of Medicine, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  1. Correspondence to Professor Philippe Dieudé, Service de Rhumatologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France; philippe.dieude{at}


Objective We recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that SPP1 may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population.

Methods Patients with RA in the ESPOIR cohort underwent genotyping for SPP1 rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed.

Results In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022).

Conclusions The SPP1 rs9138 variant contributes to joint damage progression in ACPA-negative RA.

  • Rheumatoid Arthritis
  • Ant-CCP
  • Autoantibodies
  • Gene Polymorphism
  • Early Rheumatoid Arthritis

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