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Multicenter Study
. 2012 Jul;71(7):1197-202.
doi: 10.1136/annrheumdis-2011-200901. Epub 2012 Mar 22.

IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

Roozbeh Sharif  1 , Maureen D Mayes, Filemon K Tan, Olga Y Gorlova, Laura Kathleen Hummers, Ami A Shah, Daniel E Furst, Dinesh Khanna, Javier Martin, Lara Bossini-Castillo, Emilio B Gonzalez, Jun Ying, Hilda Torres Draeger, Sandeep K Agarwal, John D Reveille, Frank C Arnett, Fredrick M Wigley, Shervin Assassi
Affiliations
Multicenter Study

IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

Roozbeh Sharif et al. Ann Rheum Dis. 2012 Jul.

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.

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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Figures

Figure 1
Figure 1
(A) Box plot of IRF5 variant (NM_001098629) gene expression levels in patients with systemic sclerosis (SSc); (B) Box plot of IRF5 variant (NM_001098629) gene expression levels in unaffected subjects; (C) Box plot of IRF5 variant (NM_032643) gene expression levels in patients with SSc; (D) Box plot of IRF5 variant (NM_032643) gene expression levels in unaffected subjects. AA, AG, and GG represent genotypes of IRF5 rs4728142
See this image and copyright information in PMC

References

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