Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity.
There is strong genetic evidence for a link between cytoplasmic RNA sensing pathways (RIG-I/MDA5) and SLE, both in human patients and murine models, however questions still remain regarding pathway initiation, cell types involved and downstream effects.
A missense mutation in <i>IFIH1</i> encoding a cytoplasmic viral RNA sensor MDA5 has recently been identified in the SMS patients as well as in patients with a monogenic form of lupus.
We concluded that IFIH1rs1990760_T and TYK2 rs2304256_C alleles were significantly associated with SLE, and IL-10 rs1800896 GG homozygote might have an enhancement effect on SLE risk.
In conclusion, IFIH1 polymorphisms (rs1990760 and rs3747517) were associated with SLE susceptibility and rs1990760 risk T allele related with IL-18 and granzyme B serum levels in SLE patients.
This longitudinal study focused on the relationship between lupus activity and the levels of intracellular proteins, phosphorylated interferon regulatory factor 7 (pIRF7), caspase-9 and -10, and mitochondrial antiviral signaling protein (MAVS) and melanoma differentiation-associated protein 5 (MDA5).
Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity.
This finding adds a new genetic causation for Mendelian lupus and greatly extends the disease spectrum associated with mutations in IFIH1 (ranging from inflammatory encephalopathy to prototypic systemic autoimmune disease).
We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection.
The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31-0.88, Pcorr.
In conclusion, our study represents the first report demonstrating an association of the IFIH1rs1990760 polymorphism with SLE susceptibility in a Chinese population.
Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
We studied the impact of the autoimmune-disease-associated IFIH1rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo.
Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (P(comb)<5×10(-8)): NCF2 (P(comb) = 2.87×10(-11)), IKZF1 (P(comb) = 2.33×10(-9)), IRF8 (P(comb) = 1.24×10(-8)), IFIH1 (P(comb) = 1.63×10(-8)), and TYK2 (P(comb) = 3.88×10(-8)).
Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease.
In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus.
A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3.
A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3.
A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3.