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Extended report
BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians
  1. B Rueda1,
  2. P Gourh2,
  3. J Broen3,
  4. S K Agarwal2,
  5. C Simeon4,
  6. N Ortego-Centeno5,
  7. M C Vonk3,
  8. M Coenen6,
  9. G Riemekasten7,
  10. N Hunzelmann8,
  11. R Hesselstrand9,
  12. F K Tan2,
  13. J D Reveille2,
  14. S Assassi2,
  15. F J Garcia-Hernandez10,
  16. P Carreira11,
  17. M Camps12,
  18. A Fernandez-Nebro13,
  19. P Garcia de la Peña14,
  20. T Nearney15,
  21. D Hilda16,
  22. M A Gónzalez-Gay17,
  23. P Airo18,
  24. L Beretta19,
  25. R Scorza19,
  26. T R D J Radstake3,
  27. M D Mayes2,
  28. F C Arnett2,
  29. J Martin1
  1. 1Instituto de Parasitologia y Biomedicina ‘Lopez-Neyra’ (CSIC), Granada, Spain
  2. 2The University of Texas Health Science Center at Houston Medical School, Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Houston, Texas, USA
  3. 3Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Servicio de Medinina Interna, Hospital Valle de Hebron, Barcelona, Spain
  5. 5Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain
  6. 6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  7. 7Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  8. 8Department of Dermatology, University of Cologne, Cologne, Germany
  9. 9Department of Rheumatology, Lund University Hospital, Lund, Sweden
  10. 10Servicio de Medicina Interna, Hospital Virgen del Rocio, Sevilla, Spain
  11. 11Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain
  12. 12Servicio de Medicina Interna, Hospital Carlos Haya, Málaga, Spain
  13. 13Servicio de Reumatología, Hospital Carlos Haya, Málaga, Spain
  14. 14Servicio de Reumatología, Hospital Ramon y Cajal, Madrid, Spain
  15. 15University of Texas Medical Branch at Galveston, Galveston, Texas, USA
  16. 16The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  17. 17Servicio de Reumatología, Hospital Xeral-Calde, Lugo, Spain
  18. 18Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia, Italy
  19. 19Referral Centre for Systemic Autoimmune Diseases, University of Milan, Milan, Italy
  1. Correspondence to Dr Blanca Rueda, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla (Granada), Spain; blarume{at}


Objective To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes.

Methods A large multicentre case–control association study including 2380 patients with SSc and 3270 healthy controls from six independent case–control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5´ allelic discrimination assay.

Results A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively).

Conclusion The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.

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  • BR, PG, JB, TRDJR, MDM, FCA and JM contributed equally to this manuscript.

  • Funding The US studies were supported by the NIH/NIAMS Center of Research Translation (CORT) in Scleroderma (P50AR054144) (FCA), the NIH/NIAMS Scleroderma Family Registry and DNA Repository (N01-AR-0-2251) (MDM), UTHSC-H Center for Clinical and Translational Sciences (Houston CTSA Program) (NIH/NCRR 3UL1RR024148) (FCA), NIH/NIAMS K08 Award (K08AR054404) (SKA), Scleroderma Foundation New Investigator Award (SKA).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the ethics committees of each participating hospital.

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

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