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Table 1 Genetic associations involving molecules of the type I interferon pathway

From: Genetic associations in type I interferon related pathways with autoimmunity

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,   [183186]
   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, 146150, 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, 141143, 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, 171173]
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, 192194]
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]
  1. 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.