The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity

Abstract

The single nucleotide polymorphism, rs1990760, in the cytosolic viral sensor, IFIH1, results in an amino-acid change (p.A946T) and is associated with multiple autoimmune diseases. The impact of this polymorphism on both viral-sensing and autoimmune pathogenesis remains poorly understood. Here, we find that human PBMCs and cell lines with the risk variant, IFIH1T946, exhibit heightened, basal and ligand-triggered type I interferon (IFN-I) production. Consistent with these findings, IFIH1T946 knock-in mice display enhanced basal IFN-I expression, survive a lethal viral challenge, and exhibit increased penetrance in autoimmune models including a combinatorial impact with other risk variants. Further, IFIH1T946 mice manifest an embryonic survival defect consistent with enhanced responsiveness to RNA self-ligands. Together, our data support a model wherein autoimmune risk variant-driven, ligand-triggered IFN-I production functions to protect against viral challenge, likely accounting for its selection within human populations, but provides this advantage at the cost of modestly promoting the risk for autoimmunity.

Phenome-wide association studies (PheWAS) across large “real-world data” population cohorts support drug target validation

“…We also identified a novel association of the IFIH1 loss-of-function allele rs1990760-C (p.T946A) with risk of asthma. The rs1990760-C allele, which protects against autoimmune diseases and increases risk of ulcerative colitis, has been shown to decrease interferon (IFN) signaling and lower resistance to viral challenge 40 , while complete loss-of IFIH1 function makes children susceptible to severe viral respiratory infections 41,42 . The association of rs1990760-C with increased risk of asthma discovered in our meta-PheWAS is consistent with the observation that bronchial epithelial cells from asthmatics produce lower amounts of IFN-β during viral infections 43 , a finding that lead to inhaled IFN-β being tested in phase 2 clinical trials for the treatment of virus-induced asthma exacerbation 44 .…”

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

“…Among all these mutations, the gain-of-function missense mutation A946T in IFIH1 (rs1990760) has been confirmed to be associated with T1DM as well as several other autoimmune diseases in several independent studies (57-59). IFIH1 A946T confers increased basal and ligand-triggered type 1 IFN expression, and transgenic mice with the A946T risk allele exhibit increased basal type 1 IFN expression (60). Additionally, several studies showed that the IFIH1 A946T risk allele exerts its effect via the IFNβ-mediated response rather than through IFN-α, and IFN-β can promote persistent LCMV (lymphocytic choriomeningitis virus) infection, which causes enduring beta-cell damage (61)(62)(63)(64)(65).…”

Developing a vaccine for type 1 diabetes by targeting coxsackievirus B

“…One such gene is Interferon Induced with Helicase C Domain 1 (IFIH1), which encodes an innate immune system receptor for EVs [88]. T1D-associated IFIH1 alleles seem to be associated with enhanced innate immune activation [91]. In addition, the polymorphisms in other innate immune system genes such as tyrosine kinase 2 (TYK2) [92,93] and those regulating the IRF7-driven innate immune system responses are also associated with increased risk of T1D [42,89].…”