ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1130

IRF8 Gene Contributes to Disease Susceptibility and Interacts with NF-KB By Modulating Interferon Signature in Patients with Systemic Sclerosis

Maria Arismendi1,2, Matthieu Giraud1, Nadira Ruzehaji1, Philippe Dieude3, Eugénie Koumakis4, Barbara Ruiz5, Paolo Airo6, Daniele Cusi7, Marco Matucci-Cerinic8, Erika Salvi9, Giovanna Cuomo10, Eric Hachulla11, Elizabeth Diot12, Paola Caramaschi13, Valeria Riccieri14, Jerome Avouac15, Cristiane Kayser16 and Yannick Allanore17, 1INSERM U1016, Paris Descartes University, Paris, France, 2Department of Rheumatology, Federal University of São Paulo, São Paulo, Brazil, 3Rhumatologie, Hopital Bichat Claude Bernard, Paris, France, 4Rheumatology A department, Cochin Hospital, Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 5Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France, 6Rheumatology and Clinical Immunology, Spedali Civili, AO Spedali Civili, Brescia, Italy, 7Department of Medicine, Surgery and Dentistry San Paolo & Genomics and Bioinformatics Platform, Fondazione Filarete, University of Milano, Milano, Italy, 8RAID working group for EULAR, Zurich, Switzerland, 9Department of Medicine, Surgery and Dentistry San Paolo & Genomics and Bioinformatics Platform, Fondazione Filarete, University of Milano, Milan, Italy, 10Department of Internal and Experimental Medicine, Second University of Naples, Naples, Italy, 11Faculté de Médecine Henri Warembourg, Université Lille Nord de France, Lille, France, 12Department of Internal Medicine, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France, Tours, France, 13Rheumatology Unit, Department of Medicine, Verona, Italy, 14Department of Internal Medicine and Medical Specialities, University Sapienza, Rome, Italy, 15Cochin Hospital, Paris, France, 16Rheumatology Division, Universidade Federal de São Paulo, São Paulo - SP, Brazil, 17Paris Descartes University, Rheumatology A Department and INSERM U1016, Cochin Hospital, Paris, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Genetics, Genomics and Proteomics II

Session Type: Abstract Submissions (ACR)

Background/Purpose . Systemic Sclerosis (SSc) is a polygenic autoimmune disease (AID) characterized by fibroblast dysregulation. It shares some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. Fibroblast dysregulation can be also observed in Primary Biliary Cirrhosis (PBC), another polygenic AID, which can be associated with SSc in the so called Reynold’s Syndrome. The present study was undertaken to investigate whether single nucleotide polymorphisms (SNPs) identified by a large GWAS in PBC might contribute to SSc susceptibility by a cross-disease approach. Methods . Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 SSc patients and 3,621 healthy controls all of whom were of European Caucasian origin. Results . We observed an association between PLCL2 rs1372072 (OR=1.23 [95% CI 1.12-1.33] Padj=7.22×10-5, NF-kB rs7665090 OR=1.16 [95% CI 1.06-1.25], Padj=0.01, and IRF8 rs11117432, OR=0.75 [95% CI 0.67-0.86], Padj=2.50×10-4 with SSc susceptibility. We subsequently queried associations according to the main subtypes and found that rs1372072 and rs11117432 were associated with the limited cutaneous subgroup (Padj=0.001 and Padj=0.003, respectively) and that rs7665090 was conversely associated with the diffuse cutaneous subset (Padj=0.007). We then looked for genotype – phenotype correlations by measuring mRNA expression of PBMC, obtained from patients (n=39) and controls (n=24), and observed that the IRF8 protective allele was associated with decreased IFIT1 expression reflecting type 1 interferon signature. We investigated gene interactions between the 3 associated SNPs that revealed an epistatic interaction between NF-kB and IRF8 SNPs (OR=0.56 [95% CI 0.00-0.74], P=4×10-4). Interestingly, we observed that the effects of IRF8 and NF-kB were only observed in patients carrying the susceptibility allele from both genes. Conclusion . By a cross disease approach querying pleiotropic genes, we identified 2 new susceptibility genes for SSc and confirmed IRF8 locus. We also identified functional effects of IRF8 variant affecting interferon signature and that an interaction between IRF8 and NF-kB genes might play a role in SSc susceptibility

Disclosure:

M. Arismendi,
None;

M. Giraud,
None;

N. Ruzehaji,
None;

P. Dieude,
None;

E. Koumakis,
None;

B. Ruiz,
None;

P. Airo,
None;

D. Cusi,
None;

M. Matucci-Cerinic,
None;

E. Salvi,
None;

G. Cuomo,
None;

E. Hachulla,
None;

E. Diot,
None;

P. Caramaschi,
None;

V. Riccieri,
None;

J. Avouac,
None;

C. Kayser,
None;

Y. Allanore,
None.

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