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Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population
  1. P Dieudé1,
  2. M Guedj2,
  3. J Wipff3,4,
  4. B Ruiz3,
  5. G Riemekasten5,
  6. M Matucci-Cerinic6,
  7. I Melchers7,
  8. E Hachulla8,
  9. P Airo9,
  10. E Diot10,
  11. N Hunzelmann11,
  12. J Cabane12,
  13. L Mouthon13,
  14. J L Cracowski14,
  15. V Riccieri15,
  16. J Distler16,
  17. O Meyer1,
  18. A Kahan4,
  19. C Boileau3,17,
  20. Y Allanore3,4
  1. 1Université Paris 7, Service de Rhumatologie, Hôpital Bichat Claude Bernard, APHP, Paris, France
  2. 2Laboratoire Statistique et Génome, UMR CNRS-8071/INRA-1152/Université d'Evry Val d'Essonne, France
  3. 3Université Paris Descartes, INSERM U781, Hôpital Necker, Paris, France
  4. 4Université Paris Descartes, Service de Rhumatologie A, Hôpital Cochin, Paris, France
  5. 5Department of Rheumatology and Clinical Immunology, Charité University Hospital, Schumannstr, Berlin, Germany
  6. 6Department of Biomedicine, Section of Rheumatology, Florence, Italy
  7. 7Clinical Research Unit for Rheumatology, University Medical Center, Freiburg, Germany
  8. 8Université Lille II, Médecine Interne, Lille, France
  9. 9Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy
  10. 10INSERM U618, IFR 135, CHU Bretonneau, Tours, France
  11. 11Department of Dermatology, University of Cologne, Köln, Germany
  12. 12Université Pierre et Marie Curie, Service de Médecine Interne, Hôpital Saint-Antoine, APHP, Paris, France
  13. 13Paris Descartes Université, Médecine Interne, Hôpital Cochin, APHP, Paris, France
  14. 14INSERM CIC3, CHU Grenoble, France
  15. 15Department of Medical Clinic and Therapy “Sapienza” University of Rome, Italy
  16. 16Department for Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany
  17. 17Université Versailles Saint Quentin Yvelines, Laboratoire de Biochimie Hormonale et Génétique, Hôpital Ambroise Paré, AP-HP, Boulogne, France
  1. Correspondence to Professor Yannick Allanore, Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France; yannick.allanore{at}


Background TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported.

Objective To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc).

Methods Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel–Haenszel meta-analysis.

Results The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10−7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10−8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10−9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10−6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10−5).

Conclusion These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.

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  • Funding This work was funded by Association des Sclérodermiques de France, INSERM, Agence Nationale pour la Recherche (Grant number R07094KS) and was supported by Groupe Français de Recherche sur la Sclérodermie. An unrestricted grant from Wyeth France supported the construction of a DNA bank for controls. The German network for systemic sclerosis was funded by the German Federal Ministry for Education and Research (Grant numbers 01 GM 0310 and 01 GM 0634 to IM, GR, NH and IT).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Paris Cochin Hospital France.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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