martes, 22 de mayo de 2012

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

  1. Javier Martin1,
+ Author Affiliations
  1. 1Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain,
  2. 2Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands,
  3. 3Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain,
  4. 4Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands,
  5. 5Servicio de Reumatología, Hospital Clínico San Carlos, Madrid, Spain,
  6. 6Servicio de Reumatología, Hospital La Princesa, Madrid, Spain,
  7. 7Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain,
  8. 8Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain,
  9. 9Servicio de Medicina Interna, Hospital Virgen del Rocio, Sevilla, Spain,
  10. 10Servicio de Reumatología, Hospital Ramón y Cajal, Madrid, Spain,
  11. 11Hospital 12 de Octubre, Madrid, Spain,
  12. 12VU University Medical Center, Amsterdam, The Netherlands,
  13. 13Department of Rheumatology, University of Leiden, Leiden, The Netherlands,
  14. 14Department of Dermatology, Josefs-Hospital, Ruhr University Bochum, Bochum, Germany,
  15. 15Hannover Medical School, Hannover, Germany,
  16. 16Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany,
  17. 17Rheumatology Unitand Chair, Spedali Civili, Università de gli Studi, Brescia, Italy,
  18. 18Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca'Granda Ospedale MaRepiore Policlinico and University of Milan, Milan, Italy,
  19. 19Department of Medicine, Policlinico GB Rossi, University of Verona, Verona, Italy,
  20. 20Department of Dermatology, University of Cologne, Cologne, Germany,
  21. 21Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen 91054, Germany,
  22. 22Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK,
  23. 23Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK,
  24. 24Department of Rheumatology and Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK,
  25. 25Centre for Rheumatology, Royal Free and University College School, London, UK and
  26. 26The University of Texas Health Science Center–Houston, Houston, TX, USA
  1. *To whom correspondence should be addressed. Email: cebercoto@ipb.csic.es
  • Received November 23, 2011.
  • Accepted March 5, 2012.

Abstract

Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10−12, odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10−7, OR = 1.36) and NFKB1 (P-value = 1.03 × 10−6, OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.

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