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Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study
  1. Lara Bossini-Castillo1,
  2. Jose Ezequiel Martin1,
  3. Jasper Broen2,
  4. Carmen P Simeon3,
  5. Lorenzo Beretta4,
  6. Olga Y Gorlova5,
  7. Madelon C Vonk2,
  8. Norberto Ortego-Centeno6,
  9. Gerard Espinosa7,
  10. Patricia Carreira8,
  11. Paloma García de la Peña9,
  12. Natividad Oreiro10,
  13. José Andrés Román-Ivorra11,
  14. María Jesús Castillo12,
  15. Miguel A González-Gay13,
  16. Luis Sáez-Comet14,
  17. Ivan Castellví15,
  18. Annemie J Schuerwegh16,
  19. Alexandre E Voskuyl17,
  20. Anna-Maria Hoffmann-Vold18,
  21. Roger Hesselstrand19,
  22. Annika Nordin20,
  23. Claudio Lunardi21,
  24. Raffaella Scorza4,
  25. Jacob M van Laar22,
  26. Paul G Shiels23,
  27. Ariane Herrick24,
  28. Jane Worthington24,
  29. Carmen Fonseca25,
  30. Christopher Denton25,
  31. Filemon K Tan26,
  32. Frank C Arnett26,
  33. Shervin Assassi26,
  34. Bobby P Koeleman27,
  35. Maureen D Mayes26,
  36. Timothy R D J Radstake2,28,
  37. Javier Martin1,
  38. the Spanish Scleroderma Group*
  1. 1Department of Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain
  2. 2Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain
  4. 4Department of Clinical Immunology and Rheumatology, Allergy, IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena and University of Milan, Milan, Italy
  5. 5Department of Epidemiology, M.D. Anderson Cancer Center, The University of Texas, Houston, Texas, USA
  6. 6Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain
  7. 7Servicio de Enfermedades Autoinmunes, Hospital Clinic, Barcelona, Spain
  8. 8Servicio de Reumatología, Hospital Universitario 12 de Octubre, Madrid, Spain
  9. 9Servicio de Reumatología, Hospital Madrid Norte Sanchinarro, Madrid, Spain
  10. 10Servicio de Reumatología, INIBIC-Hospital Universitario A Coruña, La Coruña, Spain
  11. 11Servicio de Reumatología, Hospital Universitari i Politecnic La Fe, Valencia, Spain
  12. 12Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, Spain
  13. 13Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain
  14. 14Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Zaragoza, Spain
  15. 15Servicio de Reumatología, Hospital Sant Pau, Barcelona, Spain
  16. 16Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  17. 17Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  18. 18Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
  19. 19Department of Rheumatology, Lund University, Lund, Sweden
  20. 20Karolinska Institute, Stockholm, Sweden
  21. 21Department of Medicine, Università degli Studi di Verona, Verona, Italy
  22. 22Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
  23. 23University of Glasgow, Glasgow, UK
  24. 24Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  25. 25Centre for Rheumatology, Royal Free and University College Medical School, London, UK
  26. 26Department of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center-Houston, Houston, Texas, USA
  27. 27Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  28. 28Department of Rheumatology and Clinical Immunology, Utrecht Medical Center, Utrech, The Netherlands
  29. *For members of the Spanish Scleroderma group see supplementary appendix, available online only).
  1. Correspondence to Dr Lara Bossini-Castillo, Department of Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain; larabc{at}


Introduction A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry.

Methods 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci.

Results Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets.

Conclusions These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.

  • Autoimmune Diseases
  • Systemic Sclerosis
  • Autoimmunity

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