Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


A Functional IRF5 Variant Predicts Prognosis in Patients with Systemic Sclerosis.

Sharif1,  Roozbeh, Mayes1,  Maureen D., Tan1,  Filemon K., Gorlova2,  Olga, Hummers3,  Laura K., Shah3,  Ami A., Furst4,  Daniel E.

University of Texas Health Science Center at Houston, Houston, TX
University of Texas M. D. Anderson Cancer Center, Houston, TX
University of Texas M.D. Anderson Cancer Center, Houston, TX
Johns Hopkins University, Baltimore, MD
UCLA Medical School, Los Angeles, CA
University of Michigan, Ann Arbor, MI
Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
Consejo Superior de Investigaciones Científicas (CSIC), Armilla (Granada), Spain
University of Texas Medical Branch, Galveston, TX
Univ of TX Health Sci Ctr, San Antonio, TX

Background/Purpose:

The first genome-wide association study (GWAS) in systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (non-MHC) susceptibility loci in IRF5, STAT4, and CD247 regions. Our goal was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. We also examined the effect of the IRF5 SNPs on its transcript expression in monocytes.

Methods:

We examined 1443 Caucasian patients with SSc, enrolled in the GENISOS and Scleroderma Family Registry (n=914 –discovery cohort) and The Johns Hopkins Scleroderma Cohort (n=529-replication cohort). Demographic, clinical, and serologic data were recorded. Forced vital capacity (FVC) % predicted was used as a surrogate for ILD severity. All patients were genotyped by the Illumina Human610-Quad BeadChip. Five SNPs, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome wide significance in the SSc-GWAS and were examined in the current study. The primary outcome was survival. Cox proportional hazards regression model was used for survival analysis. Then, the correlation of the investigated SNPs with FVC% predicted at enrollment was examined by linear regression. Next, we explored the effect of the three investigated IRF5 SNPs on transcript expression using gene expression microarrays. The transcript levels of IRF5 in monocytes were examined conditional on the IRF5 SNPs in SSc patients and unaffected controls.

Results:

Overall, 15.5% of the patients had died over the follow up time of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (HR: 0.76, 95%CI: 0.60–0.96, P=0.021) and in the independent replication cohort(HR: 0.73, 95%CI: 0.54–0.99, P=0.047). This SNP was also associated with better survival in the combined cohort (HR: 0.75, 95%CI: 0.62–0.90, p=0.002), which remained significant even after Bonferroni's correction (pcorr=0.01). Moreover, the impact of this SNP on survival remained significant even after adjustment for age at disease onset, disease type, and autoantibody profile (p=0.043). The minor allele frequency of IRF5 rs4728142 in the combined sample was 49.4%.

Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrollment ((b: 2.64, CI: 0.43– 4.84, P=0.019)), adjusted for disease duration. The other two IRF5 SNPs, as well as STAT4 and CD247 polymorphisms were associated neither with survival nor with ILD severity. Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p=0.014 and p=0.034, respectively), suggesting that the IRF5 rs4728142 SNP may be functionally relevant.

Conclusion:

This is the first study, linking a non-MHC genetic locus to survival and/or severity of ILD in SSc. A functional 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. This finding supports the pivotal role of IRF5 and related type I interferon pathways in SSc which could lead to identification of novel therapeutic targets and development of prognostic biomarkers.

To cite this abstract, please use the following information:
Sharif, Roozbeh, Mayes, Maureen D., Tan, Filemon K., Gorlova, Olga, Hummers, Laura K., Shah, Ami A., et al; A Functional IRF5 Variant Predicts Prognosis in Patients with Systemic Sclerosis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2429
DOI:

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