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.

Gene-Gene Interactions In Interferon Pathway Gene-Mutations In European and American Scleroderma Cohorts.

Gourh1,  Pravitt R., Tan2,  Filemon K., Rueda3,  Blanca, Arnett2,  Frank C., Assassi2,  Shervin, Reveille2,  John D., Radstake4,  Timothy RD

UTHSC-Houston Medical School, Houston, TX
University of Texas Health Science Center at Houston, Houston, TX
Facultad de Ciencias de la Salud. Universidad de Granada, Granada, Spain
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain


Tpe-I interferon(IFN), a central mediator of innate immunity, has been shown to be the hallmark peripheral blood gene expression pattern in lupus(SLE) and a similar type-I IFN signature has been noted in systemic sclerosis(SSc). Interferon regulatory factor 5 and 7(IRF5/IRF7) and tyrosine kinase 2(TYK2) are important genes involved in this signaling cascade. The purpose of this work was to investigate the association of IRF5, IRF7, TYK2 polymorphisms with SSc.


We performed SNP genotyping for IRF5(rs20024640), IRF7(rs1061502), TYK2(rs2304256) genes using the Taqman Assay in 4 large cohorts comprising of North-American Caucasian, Dutch, Italian and Spanish samples totaling to 2,091 SSc patients and 1,434 race-matched controls. All SSc patients fulfilled ACR criteria or had at least 3 of the 5 CREST features. HWE testing, chi-square, logistic regression(LR) were used for statistical comparisons. Mesoscale assays were used for cytokine detection.


After HWE verification, all 3 SNPs showed association with SSc in US Cohort with recessive pattern in IRF5 and a dominant pattern in IRF7 and TYK2. By LR analysis after controlling for gender and cohorts the association was confirmed in all cohorts{IRF5:P<0.0001,OR(CI)-0.68(0.6–0.8);IRF7:P=0.006,OR(CI)-0.80(0.7–0.9);TYK2: P=0.05,OR(CI)-0.85(0.7–0.99)}. The association was stronger with anti-centromere subset{IRF5:P=0.0002,OR(CI)-0.59(0.5–0.8);IRF7:P=0.0008,OR(CI)-0.69(0.6–0.9);TYK2:P=0.04,OR(CI)-0.79(0.6–0.9)}.

The data was modeled based on mode of inheritance for the 3 SNPs and LR analysis performed controlling for gender and cohorts and revealed an extremely protective effect for the combination of mutations vs the wildtype{IRF5M/IRF7M,TYK2M vs IRF5WT/IRF7WT,TYK2WT:P<0.0001;OR(CI)-0.39(0.3–0.6)}.

In the IRF5WT/IRF7WT,TYK2WTgroup, the SSc patients had increased levels of TNF-a and IL-6 as compared to controls and there was no difference amongst the patients and controls in the IRF5M/IRF7M,TYK2M group.


Our data confirms the association of IRF5 SNP with SSc and also demonstrates for the first time the association of IRF7 and TYK2 SNPs with SSc.

We demonstrate a gene-gene interaction in SSc between three non-linked loci- IRF5, IRF7 and TYK2.

The 3 gene-SNPs have a protective effect in SSc patients and the presence of the 3 mutations simultaneously has the most protective effect. This effect is stronger in the anti-centromere subset of SSc patients.

Plasma TNF-a and IL-6 levels were increased in the SSc patients wildtype for the 3 SNPs vs controls, whereas there was no difference in TNF-a and IL-6 levels in the SSc patients having mutations for the 3 SNPs vs controls.

In summary, IRF5,IRF7,TYK2 SNPs have a protective effect in SSc which is stronger when there are polymorphisms on all of the genes as compared to each of them alone. The presence of these 3 polymorphisms simultaneously correspond to a lower level of proinflammatory cytokine production as compared to wildtype.

This suggests an important role of interferon pathway polymorphisms in susceptibility to SSc and the exact role of these interactions and their function in SSc susceptibility needs to be elucidated experimentally.

To cite this abstract, please use the following information:
Gourh, Pravitt R., Tan, Filemon K., Rueda, Blanca, Arnett, Frank C., Assassi, Shervin, Reveille, John D., et al; Gene-Gene Interactions In Interferon Pathway Gene-Mutations In European and American Scleroderma Cohorts. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2329

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