# Protective <i>IFIH1</i> variant reduces islet stress and dysfunction in a type 1 diabetes genetic background

Article · Veronese-Paniagua DA, Banks C, Bradley K, Mukherjee N, Gale SE, Hinshaw KE, Meacham AM, Iwaloye OF, Tse HM, Mathews CE, Millman JR

- Archive id: doi:10.1016/j.isci.2026.117560
- Published: 2026-09-17
- Venue: iScience
- DOI: https://doi.org/10.1016/j.isci.2026.117560
- PMID: 42787837
- PMCID: PMC13602225
- Citations: 0
- Source URL: https://doi.org/10.1016/j.isci.2026.117560
- PDF: https://europepmc.org/articles/PMC13602225/pdf
- Provenance: europepmc

## Abstract

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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

Cited in dossiers:
- [Gene & Cell Therapy: State of the Field (October 2026)](https://space-kitty.com/dossiers/gene-cell-therapy)

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