iScienceSep 25, 2026

A protective gene variant lowers stress and damage in insulin-producing cells in type 1 diabetes

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 26, 2026

Abstract

IFIH1 E627∗ variant is associated with reduced inflammatory responses in human stem cell-derived islets.

The E627∗ variant is linked to protection from type 1 diabetes, while the A946T variant is associated with increased risk.
Stem cell-derived islets with the E627∗ variant showed significantly lower apoptosis compared to those with the A946T variant.
E627∗ SC-islets displayed reduced viral burden and mitochondrial dysfunction when exposed to inflammatory and viral stress.
Insulin secretion was less impaired in E627∗ SC-islets compared to A946T islets under stress conditions.

Simplified

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.