Table 1.
Known single nucleotide polymorphisms (SNPs) associated with RA genetic risk and how their function may affect IFN-I biology
| Gene with known RA risk variant | Role in IFN biology | Reference* |
|---|---|---|
| TNFAIP3 (A20) | • NF-κB and other A20-regulated signalling molecules can induce IFN-I | 1 |
| PADI4 | • PADI4 knockouts resulted in reduced IFN-I responses | 2 |
| STAT4 | • STAT4 promotes RIG-I signalling independent of its classical activation pathway and promotes IFN-β production in myeloid innate cells | 3 |
| CD40 | • CD40 can enhance STING-mediated IFN-I responses | 4 |
| UBE2L3 | • UBE2L3 shown to negatively regulate IFN-I expression | 5 |
| IFNAR1/IFNGR2 | • Encodes signalling receptors for IFN-I and IFN-II | 6 |
| ETS1 | • ETS-1 suggested in SLE patient studies to be associated with IFN-I and to negatively regulate ISG3 and ISRE binding sites | 7,8 |
| PVT1 |
• PVT1 negative feedback mediator for IFN-I signalling via STAT1 interaction and subsequent reduction of its phosphorylation. • IFN-α stimulation shown to upregulate PVT1 RNA expression |
9,10 |
| CDK6 | • CKD6 regulates IFN-I signalling negative feedback loops | 11 |
| ETV7 | • ETV7 negatively regulates IFN-I signalling | 12 |
| EOMES | • EOMES expression is driven by IFN-I signalling in CD8+ T cells which leads to regulation of memory-like CD8+ T cell homeostasis and function | 13 |
| TYK2 | • TYK2 required for IFN-I induced activation of transcription factors STAT1-4 and downstream signalling | 14 |
| IRF8 | • Regulates IFN-I production | 15 |
| Runx1 | • RUNX1 upregulates IFNs and IRGs via IFN-I signalling | 16 |
| RCAN1 | • RCAN1 protein stability negatively affected by IFN-α treatment via STAT2 activation | 17 |
| GATA3 |
• GATA3 overexpression promotes IFN-I expression • IFN- α/β treatment suppresses GATA3 expression |
18,19 |
| DDX6 |
• DDX6 regulates RIG-I mediated IFN-I signalling • DDX6 depletion leads to increased IRG expression |
20,21 |
| PRDM1 |
• Deletion results in impaired IFN-I production • Control IKKα and IRF7 activation via direct suppression of Irak3, a negative regulator of TLR signalling |
23 |
| IRF5 |
• IRF5 shown to a positive regulator of IFN-I signalling • Risk haplotype of IRF5 associated with SLE and with increased IFN-I production |
24 |
*Separate reference list in supplementary file 1.