Autoimmune Disease Risk Variant of IFIH1 Is Associated with Increased Sensitivity to IFN-α and Serologic Autoimmunity in Lupus Patients

Abstract

Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease–associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α–induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA–positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 Tallele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.

Meta-analysis of STAT4 and IFIH1 polymorphisms in type 1 diabetes mellitus patients with autoimmune polyglandular syndrome type III

“…IFIH1 is a helicase that senses viral dsRNA and, when activated, supports the transcription of IFN-I and IFN-induced genes (Robinson et al, 2011). Since IFIH1 acts during viral infections, we hypothesized in a previous publication that a defective mechanism in virus recognition might be caused by a defective IFIH1 (Moura et al, 2013).…”

Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility

“…Its risk allele is associated with a lower IFN-a level, but enhanced IFN-induced gene expression in the SLE patients who carry anti-dsDNA antibodies. 31 In addition, this allele is associated with a higher expression level of the IFIH1 gene itself. 25 IFIH1 is located in a high LD region that is shared by the genes fibroblast activation protein alpha (FAP) and grancalcin EF-hand calcium binding protein (GCA) (Supplementary Figure 3b).…”

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…Intriguingly, high IFN-I activity seems to be a heritable risk factor being clustered in specific families in both SLE patients and their healthy first-degree relatives (49). The risk haplotypes in the interferon regulatory factors IRF5 and IRF7 are associated with increased IFN-I activity and the risk is dependent on particular autoantibodies (53)(54)(55)(56)(57)(58). The risk haplotype of IRF5 is also associated with risk of progression to clinical disease in ANA positive individuals (56).…”