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Extended report
The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases
  1. Fina A S Kurreeman1,
  2. George N Goulielmos2,
  3. Behrooz Z Alizadeh3,
  4. Blanca Rueda4,
  5. Jeanine Houwing-Duistermaat5,
  6. Elena Sanchez4,
  7. Marianna Bevova3,
  8. Timothy R Radstake6,
  9. Madelon C Vonk6,
  10. Emmanouil Galanakis2,
  11. Norberto Ortego7,
  12. Willem Verduyn8,
  13. Maria I Zervou2,
  14. Bart O Roep8,
  15. Barbara Dema9,
  16. Laura Espino9,
  17. Elena Urcelay9,
  18. Dimitrios T Boumpas2,
  19. Leonard H van den Berg10,
  20. Cisca Wijmenga3,11,
  21. Bobby P C Koeleman3,
  22. Tom W J Huizinga1,
  23. Rene E M Toes1,
  24. Javier Martin4
  25. the AADEA Group and SLEGEN Consortium
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Medicine, University of Crete, Greece
  3. 3Department of Biomedical Genetics, Utrecht University Medical Center, Utrecht, The Netherlands
  4. 4Instituto de Biomedicina López-Neyra, CSIC, Granada, Spain
  5. 5Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  7. 7Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain
  8. 8Department of Immunohaematology and Bloodbank, Leiden University Medical Center, Leiden, The Netherlands
  9. 9Department of Immunology, Hospital Clínico San Carlos, Madrid, Spain
  10. 10Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
  11. 11Department of Human genetics, Groningen University Medical Center and University of Groningen, Groningen, The Netherlands
  1. Correspondence to Rene E M Toes, Department of Rheumatology, C1R, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; r.em.toes{at}lumc.nl

Abstract

Objectives The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE).

Methods The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete.

Results A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6×10−4), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02×10−6) in a total of 1577 patients with SLE and 4215 healthy individuals.

Conclusion A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases.

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Footnotes

  • GNG and BZA contributed equally.

  • Participants The AADEA (Andalusian Association of Autoimmune Diseases) Group participants are as follows: Juan Jiménez-Alonso (Servicio Medicina Interna, Hospital Virgen de las Nieves, Granada); Julio Sanchez-Román (Servicio de Medicina Interna, Hospital Virgen del Rocio, Sevilla); Enrique De-Ramon and Mayte Camps (Servicio Medicina Interna, Hospital Carlos Haya, Málaga); M Angeles Aguirre (Servicio de Reumatología, Hospital Reina Sofía, Córdoba); Rosa García-Portales (Servicio Medicina Interna, Hospital Virgen de la Victoria, Málaga). The SLEGEN consortium members are as follows: John B Harley, Lindsey A Criswell, Timothy Vyse, Robert Kimberly, Chaim Jacob, Kathy Moser, Carl Langfeldt, Marta E Alarcón-Riquelme and Betty Tsao.

  • Funding This study was supported by grants from the Dutch Arthritis Foundation, grant SAF2006–00398 from the Spanish Ministerio de Educacion y Ciencia, grant CTS1180 from Junta de Andalucía, the European Community's FP6 funding project 018661 Autocure and the Center for Medical Systems Biology in The Netherlands. Support was also obtained from funding for a VIDI grant for REMT and VICI grant 918–66-620 from the Dutch organisation for scientific research (NWO) as well as the Celiac Disease Consortium (an innovative cluster approved by The Netherlands Genomics Initiative and partly funded by the Dutch government (grant BSIK03009)).

  • Competing interests None.

  • Ethics approval Informed consent was obtained from all subjects and the study was approved by the local ethics committee of each centre.

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

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