title: IRF5 polymorphism predicts prognosis in patients with systemic sclerosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Sharif
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Olga Y
authors.initials: OY
authors.lastname: Gorlova
authors.forename: Laura Kathleen
authors.initials: LK
authors.lastname: Hummers
authors.forename: Ami A
authors.initials: AA
authors.lastname: Shah
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Lara
authors.initials: L
authors.lastname: Bossini-Castillo
authors.forename: Emilio B
authors.initials: EB
authors.lastname: Gonzalez
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.forename: Hilda Torres
authors.initials: HT
authors.lastname: Draeger
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Wigley
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
mesh_terms: D000328:Adult; D017668:Age of Onset; D015415:Biomarkers / Q000378:metabolism; D015897:Comorbidity; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012042:Registries; D012595:Scleroderma, Systemic / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D012720:Severity of Illness Index; D015996:Survival Rate; D014481:United States / Q000453:epidemiology; D014797:Vital Capacity
chemical_list: D015415:Biomarkers; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors