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Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis
  1. F David Carmona1,
  2. Ramana Gutala2,
  3. Carmen P Simeón3,
  4. Patricia Carreira4,
  5. Norberto Ortego-Centeno5,
  6. Esther Vicente-Rabaneda6,
  7. Francisco J García-Hernández7,
  8. Paloma García de la Peña8,
  9. Mónica Fernández-Castro9,
  10. Lina Martínez-Estupiñán10,
  11. María Victoria Egurbide11,
  12. Betty P Tsao12,
  13. Pravitt Gourh2,
  14. Sandeep K Agarwal2,
  15. Shervin Assassi2,
  16. Maureen D Mayes2,
  17. Frank C Arnett2,
  18. Filemon K Tan2,
  19. Javier Martín1,
  20. Spanish Scleroderma Group
  1. 1Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain
  2. 2Department of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center, Houston, Texas, USA
  3. 3Department of Internal Medicine, Hospital Valle de Hebron, Barcelona, Spain
  4. 4Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain
  5. 5Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain
  6. 6Department of Rheumatology, Hospital de la Princesa, Madrid, Spain
  7. 7Department of Internal Medicine, Hospital Virgen del Rocío, Sevilla, Spain
  8. 8Department of Rheumatology, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain
  9. 9Department of Rheumatology, Hospital Puerta de Hierro, Madrid, Spain
  10. 10Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  11. 11Department of Internal Medicine, Hospital de Cruces, Barakaldo, Spain
  12. 12Division of Rheumatology, University of California, Los Angeles, California, USA
  1. Correspondence to F David Carmona, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain; dcarmona{at}


Objective Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.

Methods Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc.

Results Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=3.83 × 10−3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant.

Conclusions The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.

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  • FDC and RG contributed equally to this work.

  • FKT and JM are joint senior authors.

  • Funding This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009–11110 from the Spanish Ministry of Science, CTS-4977 and CTS-180 from Junta de Andalucía, RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain, within the VI PN de I+D+i 2008–2011 (FEDER), and is sponsored by the Orphan Disease Program grant from EULAR. NO and JM are funded by Consejería de Salud, Junta de Andalucía through PI-0590–2010. FDC was supported by Consejo Superior de Investigaciones Científicas (CSIC) through the program JAE-DOC. The US analyses were supported by US National Institutes of Health and the National Institute of Arthritis and Musculoskeletal Diseases (NIH-NIAMS) R01-AR-055258, Two-Stage Genome Wide Association Study in Systemic Sclerosis (MDM) and by the NIH-NIAMS Center of Research Translation (CORT) in SSc (P50AR054144) (MDM, FCA, FKT), the NIH-NIAMS SSc Family Registry and DNA Repository (N01-AR-0-2251) (MDM), NIH-NIAMS K08 Award (K08AR054404) (SKA), SSc Foundation New Investigator Award (SKA), NIH-KL2RR024149-04 (SA) and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111) (MDM).

  • Competing interests None.

  • Ethics approval Ethical approval was obtained from the Committee for the Protection of Human Subjects of the University of Texas Health Science Center at Houston (USA) and the Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (Granada, Spain) and informed written consent was obtained from all participants in accordance with the tenets of the Declaration of Helsinki.

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

    Members of the Spanish Scleroderma Group are shown in the online supplement.