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Extended report
IRF5 polymorphism predicts prognosis in patients with systemic sclerosis
  1. Roozbeh Sharif1,
  2. Maureen D Mayes2,
  3. Filemon K Tan2,
  4. Olga Y Gorlova3,
  5. Laura Kathleen Hummers4,
  6. Ami A Shah4,
  7. Daniel E Furst5,
  8. Dinesh Khanna6,
  9. Javier Martin7,
  10. Lara Bossini-Castillo7,
  11. Emilio B Gonzalez8,
  12. Jun Ying3,
  13. Hilda Torres Draeger9,
  14. Sandeep K Agarwal2,
  15. John D Reveille2,
  16. Frank C Arnett2,
  17. Fredrick M Wigley4,
  18. Shervin Assassi2
  1. 1Division of Rheumatology and Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  2. 2Department of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  3. 3Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
  4. 4Department of Medicine/Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  5. 5Department of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA
  6. 6Division of Rheumatology/Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  7. 7Department of Immunology, Instituto de Biomedicina Lopez-Neyra. CSIC, Granada, Spain
  8. 8Division of Rheumatology/Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
  9. 9Division of Rheumatology/Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  1. Correspondence to Dr Shervin Assassi, Division of Rheumatology, The University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5.232, Houston, TX 77030, USA; shervin.assassi{at}


Objective The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.

Methods The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study.

Results Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%.

Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant.

Conclusion An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

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  • Funding The study was supported by the National Institute of Health. N01-AR-2251; R01-AR055258; P50-AR-054144; KL2-RR-024149; K23-AR-061436; T32-AR-052283; M01-RR-00073; M01-RR-01346; UL1-RR-024148; TL1-RR-024147.

  • Competing interests LKH is a consultant for NexMed and Amira; receives grant support from Actelion, United Therapeutics, Novartis and Medimmune. FMW is a consultant for Amira, Novartis and Orion; advisory board member for Orion Phamaceuticals; received grant support from United Therapeutics and Actelion. DK has received grant support from Takeda, URL and Savient; consultant for Novartis, Ardea, Takeda and Savient; on the speakers bureau of Takeda and Savient; received support for travel expenses from Takeda, Novartis and Savient. DEF has received grants from, is a consultant and scientific review board member for Actelion, Gilead and Roche/Genetech. Actelion, Pfizer and Medimmune have provided grants to the institution where AAS works. RS, MDM, FKT, OYG, JM, LB-C, EBG, HTD, JY, SKA, JDR, FCA and SA declare no competing interest.

  • Ethics approval Institutional Review Board of the pariticipating sites.

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