Abstract
Systemic lupus erythematosus (SLE) has heterogeneous clinical manifestations. IFIH1 (interferon induced with helicase C domain 1) as one of antiviral helicase genes mediating type I interferon production, plays an essential role in the pathogenesis of SLE. The gene variants in IFIH1 could abnormally activate antiviral defenses and increased type I interferon signaling. The present study aimed to validate associations between single nucleotide polymorphisms (SNP) in IFIH1 and the pathogenesis of SLE. In total, rs1990760, rs3747517 and rs10930046 in IFIH1 are genotyped in 400 SLE patients and 659 health controls in Chinese cohort by an improved multiplex ligation detection reaction (iMLDR) technique. Significant associations were observed between alleles of IFIH1 (rs1990760 C > T, P = 0.005, OR = 1.36, 95%CI = 1.10–1.69; rs3747517 T > C, P = 0.004, OR = 1.31, 95%CI = 1.09–1.58, respectively) and SLE susceptibility. IFIH1 rs1990760 TT genotype carriers had lower serum levels of IL-18 (P < 0.001) and granzyme B (P < 0.001) than CC and CT genotype carriers. IFIH1 rs1990760 CT genotype carriers had higher anti-dsDNA–positive than CC and TT genotype carriers. 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.
Highlights
Systemic lupus erythematosus (SLE) is a systemic multiorgan autoimmune disease which is characterized by chronic inflammation mediated by diversified immunologic factors
Our study first focused on the associations between IFIH1 variants and SLE susceptibility and the serum levels of inflammatory markers (IL-18 and granzyme B) in Chinese SLE patients
Type I IFN and proinflammatory cytokines have a great influence on the pathogenesis and severity of SLE14–16
Summary
Systemic lupus erythematosus (SLE) is a systemic multiorgan autoimmune disease which is characterized by chronic inflammation mediated by diversified immunologic factors. As one of the antiviral helicase genes mediating type I interferon production, IFIH1 (interferon induced with helicase C domain 1) may play an essential role both in the pathogenesis and progression of SLE7. As a member of the retinoic acid-inducible gene I (RIG-I) -like receptor family, the IFIH1 protein known as MDA5 (melanoma differentiation-associated protein 5), is highly upregulated in activated immune cells in response to type I interferon and is expressed at lower levels in resting immune cells and other tissues, including pancreatic islets[8]. Previous GWAS on IFIH1 identified the association between few SNPs in this gene with the risk of various autoimmune diseases including type 1 diabetes (T1DM), multiple sclerosis, psoriasis, selective IgA deficiency, dilated cardiomyopathy and SLE11,12. The T risk allele at rs1990760 can increase the expression of IFIH1 gene and regulate the production of type I IFN and various proinflammatory cytokines www.nature.com/scientificreports/. We found that these SNPs had a stronger magnitude of increased risk for SLE and associated with serum levels of IL-18 and granzyme B
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