Protective IFIH1 variant reduces islet stress and dysfunction in a type 1 diabetes genetic background

Genome-wide association studies have identified IFIH1, which encodes the double-stranded RNA sensor MDA5, as a type 1 diabetes (T1D) risk locus. The IFIH1 E627∗ variant is associated with protection from T1D, whereas A946T is associated with increased risk. To examine how these variants influence islet responses to inflammatory and viral stress, we used CRISPR-Cas9 to engineer E627∗ or A946T into human pluripotent stem cells from a T1D donor and differentiated them into stem cell-derived islets (SC-islets). SC-islets were exposed to IFNα, poly(I:C), or coxsackievirus B3 and analyzed by single-cell RNA sequencing and functional assays. E627∗ SC-islets compared to A946T displayed reduced inflammatory and stress responses with lower apoptosis, viral burden, mitochondrial dysfunction, and insulin secretory impairment. These findings support a protective role for IFIH1 E627∗ in human islet responses to inflammatory and viral stress and provide insight into genetic mechanisms potentially linked to T1D pathogenesis.