Table 1.
Genetic associations involving molecules of the type I interferon pathway
| Chromosome | Gene | Associated polymorphisms | Disease/trait | Functional effect (if demonstrated) | References |
|---|---|---|---|---|---|
| Genes with strong evidence of association and/or good replication studies | |||||
| 1q21-24 | FCGR2A | rs1801274 (R131H) | SLE, PAPS | R131 has lower affinity to IgG2, which may affect the clearance of immune complexes | [85,105,106] |
| 2q24.3 | IFIH1 (MDA-5) | rs1990760 (T946A), | T1D, RA, | [183-186] | |
| rs3747517 (R843H) | MS, GD | ||||
| rs35337543 (G>C), | T1D | E627X and I923V are loss of function mutations. | [10,187] | ||
| rs35667974 (I923V), | E627X results in deletion of the C-terminal region necessary for dsRNA binding activity. I923V alters a conserved residue, which might impair the signaling | ||||
| rs35744605 (E627X), | |||||
| rs35732034 (G>A) | |||||
| 7q32 | IRF5 | CGGGG promoter insertion/deletion, rs2004640, exon 6 insertion/deletion rs10954213 | RA, T1D, SLE, IBD, pSS | CGGGG and rs10954213 risk alleles enhance expression levels of IRF5. SNP rs2004640 and exon 6 insertion/deletion determine alternative splice isoforms | [68,70,72,74,75,78,188] |
| 2q32.2 | STAT4 | rs7574865, rs7568275, rs3821236, rs10168266 | RA, SLE, pSS, psoriasis, PAPS | Risk haplotype associated with high levels of expression and greater sensitivity to IFNα | [144,146-150,164,169,189,190] |
| 9p13.2 | TYK2 | rs2304256, rs12720270, rs34536443 | SLE, MS | rs12720270 located in a intron/exon boundary might be involved in alternative splicing | [69,141-143,149] |
| 8p23-p22 | BLK | rs13277113, rs2736340 | SLE, PAPS | Promoter SNPs associated with reduced expression of BLK | [145,149,169] |
| 4q24 | BANK1 | rs10516487 (R61H), rs17266594, rs3733197 (A383T) | SLE, RA | rs17266594 determines the transcription ratio between the full-length and delta 2 isoforms | [149,166,171-173] |
| Good evidence | |||||
| 1q21-24 | FCGR3B | NA1/NA2, CNV of the whole gene | SLE, mPA, WG | NA1-homozygous has stronger FcγR-mediated phagocytic response. Increased risk for SLE with <2 gene copies | [107] |
| 4q21-q25 | SPP1 | rs1126616, rs1126772, rs9138, rs7687316 | 3'-UTR polymorphisms associated with high amounts of ostepontin and IFNα in sera of patients with SLE. Evidence of rs9138-gender interaction | [130,131,136,137] | |
| 5q32-q33.1 | TNIP1 | rs10036748, rs7708392 | SLE | No functional polymorphism yet identified. TNIP1 is the A20-binding inhibitor of NF-κB activation and together with A-20 serves as brake for interferon production induced via TLR | [86,136,191] |
| rs17728338 | Psoriasis | ||||
| 16p13.3 | DNASEI | V89M, K5X, 46_72 deletion, rs179982-rs1030874-rs1059857 haplotype,. | SLE, AITD | V89M and K5X are associated with lower enzymatic activity. Haplotype rs179982-rs1030874-rs1059857 defines isoforms of DNaseI | [179,192-194] |
| 3p21.31 | TREX1 (DNASEIII) | R114H, 158V, P212fs, G227S, R240S, A247, P272fs, P290L, Y305C, G306A | SLE, pSS | R114H associated with decreased exonuclease activity. Frameshift mutations D272fs and P212fs alter subcellular localization of the protein | [180,181] |
| Good evidence but more replication studies are required | |||||
| 2p13-p12 | REL | rs13031237, rs13017599 | RA | [93] | |
| 3q13.11 | CBLB | F328L | T1D | [195] | |
| 1q21-24 | FCGR3A | rs396991, V176F | Lupus nephritis | [105] | |
| 1q21-24 | FCGR2B | I232T | SLE | [105] | |
| 8q13 | LYN | rs6983130 | SLE | [85,176] | |
| 5q31.1 | IRF1 | rs2070721 | MS, JIA | [161,196] | |
| 2q.36 | IRS1 | rs1801278, G972R | T1D | [197] | |
| 16q24.1 | IRF8 | rs17445836 | MS | [90] | |
| 2q32.2 | STAT1 | rs2066802, rs1547550 | MS | [161] | |
| 11q24.2 | TIRAP | rs8177374, S180L | SLE, IBD | [198,199] | |
| Good evidence but more replication studies are required | |||||
| 6q21 | ATG5 | rs6568431 | SLE | [85] | |
| Xq28 | IRAK1 | rs2239673-rs763737-rs5945174-rs7061789 GGGG haplotype | SLE | [200] | |
| Inconsistent replication | |||||
| 9q32-q33 | TLR4 | rs4986790 (G299D) | RA, GCA | [201,202] | |
| 9p22 | IFNA gene cluster | SLE, MS | [203,204] | ||
| 21q22.11 | IFNAR cluster | IFNAR1:18417, IFNAR2: 11876 | MS | [205] | |
| 4q24 | NFKB1 | -94 ATTG insertion/deletion, CA microsatellite | T1D, UC, GD | [99,101] | |
| 3p21.3 | TLR9 | +1174 A>G | SLE | [206] | |
| 17q21 | STAT3 | rs744166, rs12948909 | CD | [162] | |
| 19q13.3-q13.4 | IRF3 | rs2304204, rs2304206 | SLE | [88] | |
Alleles associated with increased risk to develop the disease are underlined (alleles over-represented in patients). SLE, systemic lupus erythematosus; PAPS, primary anti-phospholipid syndrome; T1D, type 1 diabetes; RA, rheumatoid arthritis; MS, multiple sclerosis; GD, Graves' disease; IBD, inflammatory bowel disease; pSS, primary Sjögren's syndrome; mPA, microscopic polyangiitis; WG, Wegener's granulomatosis; AITD, autoimmune thyroid diseases; JIA, juvenile idiopathic arthritis; GCA, giantcell arteritis; UC, ulcerative colitis; CD, Crohn's disease.