The Type 1 Diabetes-Associated Single Nucleotide Polymorphism rs1990760 in IFIH1 Is Associated with Increased Basal Type I IFNs and IFN-stimulated Gene Expression

Type 1 diabetes (T1D) is a chronic autoimmune disease that is caused by a combination of genetic and environmental risk factors. In this study, we sought to determine whether a known genetic risk factor, the rs1990760 single nucleotide polymorphism (SNP) (A946T) in IFIH1, resulted in a gain of function in the MDA5 protein and the effects of this mutation on the regulation of type I IFNs during infection with the diabetogenic virus coxsackievirus B3. We found that in cell lines overexpressing the risk variant IFIH1946T there was an elevated level of basal type I IFN signaling and increased basal IFN-stimulated gene expression. An investigation into the mechanism demonstrated that recombinant MDA5 with the A946T mutation had increased ATPase activity in vitro. We also assessed the effect of this SNP in primary human PBMCs from healthy donors to determine whether this SNP influenced their response to infection with coxsackievirus B3. However, we observed no significant changes in type I IFN expression or downstream induction of IFN-stimulated genes in PBMCs from donors carrying the risk allele IFIH1946T. These findings demonstrate the need for a deeper understanding of how mutations in T1D-associated genes contribute to disease onset in specific cellular contexts. The Journal of Immunology, 2024, 213: 1415-1428.