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

Maria Arismendi^1,2, 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: polymorphism and systemic sclerosis

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] P_adj=7.22×10^-5, NF-kB rs7665090 OR=1.16 [95% CI 1.06-1.25], P_adj=0.01, and IRF8 rs11117432, OR=0.75 [95% CI 0.67-0.86], P_adj=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 (P_adj=0.001 and P_adj=0.003, respectively) and that rs7665090 was conversely associated with the diffuse cutaneous subset (P_adj=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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