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.