title: SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis.
abstract: 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.
authors.affiliation: Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Juge
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hanna W
authors.initials: HW
authors.lastname: van Steenbergen
authors.affiliation: UMR 1027, INSERM, Toulouse III University and Department of Rheumatology, Purpan Hospital, CHU Toulouse, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Constantin
authors.affiliation: Department of Rheumatology, Morvan Hospital, Cavale Blanche Hospital, Brittany University, Brest, France.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Tobon
authors.affiliation: Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Schaeverbeke
authors.affiliation: Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.affiliation: Department of Rheumatology, Montpellier University Hospital, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Combe
authors.affiliation: Department of Rheumatology, Morvan Hospital, Cavale Blanche Hospital, Brittany University, Brest, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Devauchelle-Pensec
authors.affiliation: UMR 1027, INSERM, Toulouse III University and Department of Rheumatology, Purpan Hospital, CHU Toulouse, Toulouse, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Nigon
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.affiliation: Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France INSERM U699, Bichat Faculty of Medicine, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieude
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D050823:Hand Joints / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics*; D010456:Peptides, Cyclic / Q000276:immunology*; D011859:Radiography
chemical_list: D001323:Autoantibodies; D010456:Peptides, Cyclic; C506895:SPP1 protein, human; C487763:cyclic citrullinated peptide; D053495:Osteopontin
keywords: Ant-CCP; Autoantibodies; Early Rheumatoid Arthritis; Gene Polymorphism; Rheumatoid Arthritis