The type 1 diabetes-associated A946T single nucleotide polymorphism in IFIH1 results in increased type I interferon signaling

Abstract

Abstract Single nucleotide polymorphisms (SNP) in the human IFIH1 gene are associated with autoimmunity and interferonopathies. The rs1990760 SNP, which results in an amino acid change from alanine to threonine at position 946 (A946T), is associated with several autoimmune diseases including rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (T1D). IFIH1 encodes for melanoma differentiation-associated protein 5 (MDA5), a cytoplasmic dsRNA sensor. Viral infections have been implicated as environmental triggers in autoimmune diseases. In T1D, Coxsackievirus B (CVB) infections are associated with disease onset and an IFN gene signature is detected shortly before the development of autoantibodies. Interestingly, MDA5 is responsible for detecting dsRNA replication intermediates formed during CVB replication. The objective of this study is to determine the interplay of a genetic risk factor (A946T SNP) and an environmental factor (CVB infections) in the initiation of T1D. We hypothesize that the A946T SNP results in exacerbated signaling and increased production of type I IFNs and inflammatory cytokines during CVB infections. To test this, we infected peripheral blood mononuclear cells (PBMCs) from healthy donors that were genotyped for the A946T SNP and measured the subsequent IFN response. We found that the expression of type I IFNs was increased at baseline in cells homozygous for the A946T SNP in contrast to without the SNP. Overexpression of the A946T SNP also led to increased basal expression of type I IFNs and IFN-stimulated genes in βLox5 cells and a type I IFN reporter cell line. This increased basal expression of type I IFNs may lead to β-cell stress and hyperreactive immune cells and contribute to the initiation of T1D.