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Genetic variation in the nuclear factor κB pathway in relation to susceptibility to rheumatoid arthritis
  1. R Dieguez-Gonzalez1,
  2. S Akar1,
  3. M Calaza1,
  4. E Perez-Pampin1,
  5. J Costas2,
  6. M Torres2,
  7. J L Vicario3,
  8. M L Velloso4,
  9. F Navarro5,
  10. J Narvaez6,
  11. B Joven7,
  12. G Herrero-Beaumont8,
  13. I Gonzalez-Alvaro9,
  14. B Fernandez-Gutierrez10,
  15. A R de la Serna11,
  16. L Carreño12,
  17. J Lopez-Longo12,
  18. R Caliz13,
  19. M D Collado-Escobar13,
  20. F J Blanco14,
  21. C Fernandez-Lopez14,
  22. A Balsa15,
  23. D Pascual-Salcedo16,
  24. J J Gomez-Reino1,
  25. A Gonzalez1
  1. 1
    Laboratorio de Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
  2. 2
    National Genotyping Center, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
  3. 3
    Regional Transfusion Center, Madrid, Spain
  4. 4
    Rheumatology Unit, Hospital Universitario de Valme. Sevilla, Spain
  5. 5
    Rheumatology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain
  6. 6
    Rheumatology Unit, Hospital Universitario de Bellvitge, Barcelona, Spain
  7. 7
    Rheumatology Unit, Hospital 12 de Octubre, Madrid, Spain
  8. 8
    Rheumatology Unit, Fundacion Jimenez Diaz, Madrid, Spain
  9. 9
    Rheumatology Unit, Hospital Universitario de la Princesa, Madrid, Spain
  10. 10
    Rheumatology Unit, Hospital Clinico San Carlos, Madrid, Spain
  11. 11
    Rheumatology Unit, Hospital Santa Creu e San Pau, Barcelona, Spain
  12. 12
    Rheumatology Unit, Hospital Universitario Gregorio Marañon, Madrid, Spain
  13. 13
    Rheumatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain
  14. 14
    Laboratorio de Investigación Osteoarticular y del Envejecimiento, Servicio de Reumatología, Hospital Universitario Juan Canalejo, A Coruña, Spain
  15. 15
    Rheumatology Unit, Hospital La Paz, Madrid, Spain
  16. 16
    Immunology, Hospital La Paz, Madrid, Spain
  1. A Gonzalez, Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, Travesia de Choupana sn., 15706-Santiago de Compostela, Spain; Antonio.Gonzalez.Martinez.Pedrayo{at}


Objective: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)κB pathway, the major intracellular pathway in RA pathogenesis.

Methods: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFκB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5′-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls.

Results: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant.

Conclusion: We did not find any major effect among the explored members of the NFκB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.

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  • Competing interests: None.

  • Funding: This project was supported by grant PI04/1513 from the Instituto de Salud Carlos III (Spain) with participation of funds from FEDER (European Union). SA was the recipient of a Research Fellowship of the Fundation Articulum.

  • Ethics approval: The Ethical Committee for Clinical Research of Galicia approved this study and all participants gave their written informed consent.

  • ▸ Additional data (supplementary tables 1–6) are published online only at