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

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 7.2210 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 2.5010 4 with SSc susceptibility. We subsequently queried associations according to the main subtypes and found that S496 Monday, November 17 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 410 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.