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Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene
  1. Steven Gazal1,
  2. Karim Sacre2,
  3. Yannick Allanore3,4,
  4. Maria Teruel5,
  5. Alison H Goodall6,
  6. (The CARDIOGENICS consortium),
  7. Shigeto Tohma7,
  8. Lars Alfredsson8,
  9. Yukinori Okada9,10,11,
  10. Gang Xie12,
  11. Arnaud Constantin13,
  12. Alejandro Balsa14,
  13. Aya Kawasaki15,
  14. Pascale Nicaise16,
  15. Christopher Amos17,
  16. Luis Rodriguez-Rodriguez18,
  17. Gilles Chiocchia4,
  18. Catherine Boileau19,
  19. Jinyi Zhang12,
  20. Olivier Vittecoq20,
  21. Thomas Barnetche21,
  22. Miguel A Gonzalez Gay22,
  23. Hiroshi Furukawa7,
  24. Alain Cantagrel13,
  25. Xavier Le Loët20,
  26. Takayuki Sumida23,
  27. Margarita Hurtado-Nedelec24,25,
  28. Christophe Richez21,
  29. Sylvie Chollet-Martin16,
  30. Thierry Schaeverbeke21,
  31. Bernard Combe26,
  32. Liliane Khoryati21,
  33. Baptiste Coustet27,
  34. Jammel El-Benna24,
  35. Katherine Siminovitch12,
  36. Robert Plenge28,
  37. Leonid Padyukov29,
  38. Javier Martin5,
  39. Naoyuki Tsuchiya15,
  40. Philippe Dieudé27,30
  1. 1Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  2. 2Department of Internal Medicine, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, INSERM U699, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  3. 3Department A of Rheumatology, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris Descartes Paris, France
  4. 4INSERM U1016, University of Paris Descartes, Cochin Hospital, Paris, France
  5. 5Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain
  6. 6Department of Cardiovascular Sciences, University of Leicester & Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK
  7. 7Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  8. 8Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  9. 9Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  10. 10Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  11. 11Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  12. 12Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  13. 13Department of Rheumatology, UMR 1027, INSERM, Toulouse III University, Purpan Hospital, CHU Toulouse, Toulouse, France
  14. 14Department of Rheumatology, Hospital La Paz, Madrid, Spain
  15. 15Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan
  16. 16Department of Immunology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  17. 17Genomic Medicine Department of Community, Family Medicine Geisel School of Medicine, Dartmouth College, USA
  18. 18Department of Rheumatology, Hospital Clinico, Madrid, Spain
  19. 19INSERM U698, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  20. 20Department of Rheumatology, CHU de Rouen-Hopitaux de Rouen and INSERM U905, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy, France
  21. 21Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France
  22. 22Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain
  23. 23Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan
  24. 24INSERM U773 CRB3, F-75018, Paris, France
  25. 25Department of Hematology and Immunology, UF Dysfonctionnements Immunitaires Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  26. 26Department of Rheumatology, Montpellier University Hospital, Montpellier, France
  27. 27Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
  28. 28Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA
  29. 29Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  30. 30Bichat Faculty of Medicine, INSERM U699, 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}bch.aphp.fr

Abstract

Objective To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the rheumatoid arthritis (RA) genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals.

Methods We analysed a total of 11 715 RA cases and 26 493 controls from nine independent cohorts; all individuals were genotyped or had imputed genotypes for SPP1 rs11439060 and rs9138. The effect of the SPP1 rs11439060 and rs9138 risk-allele combination on osteopontin (OPN) expression in macrophages and OPN serum levels was investigated.

Results We provide evidence for a distinct contribution of SPP1 to RA susceptibility according to ACPA status: the combination of ≥3 SPP1 rs11439060 and rs9138 common alleles was associated mainly with ACPA negativity (p=1.29×10−5, ORACPA-negative 1.257 (1.135 to 1.394)) and less with ACPA positivity (p=0.0148, ORACPA-positive 1.072 (1.014 to 1.134)). The ORs between these subgroups (ie, ACPA-positive and ACPA-negative) significantly differed (p=7.33×10−3). Expression quantitative trait locus analysis revealed an association of the SPP1 risk-allele combination with decreased SPP1 expression in peripheral macrophages from 599 individuals. To corroborate these findings, we found an association of the SPP1 risk-allele combination and low serum level of secreted OPN (p=0.0157), as well as serum level of secreted OPN correlated positively with ACPA production (p=0.005; r=0.483).

Conclusions We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association being greater in patients negative for ACPAs.

  • Rheumatoid Arthritis
  • Ant-CCP
  • Gene Polymorphism

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