# Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $1,190,423

## Abstract

Project Summary/Abstract
Type 1 diabetes (T1D) is a multifactorial autoimmune disease that requires genetic susceptibility as
well as environmental triggers such as viral infections in triggering disease onset. One viral infection
that is highly correlated with T1D is the Coxsackievirus B (CVB) serotype. Sensing of CVB is
mediated by the melanoma differentiation-associated protein 5 (MDA5), a cytosolic sensor of dsRNA,
which is encoded by the IFIH1 gene. Stimulation of the MDA5 signaling pathway activates the
transcription factors IRF3 and NF-κB p65, which induce Type I IFNs synthesis, which through
autocrine signaling initiate an antiviral transcriptional program. Single nucleotide polymorphisms
(SNPs) in the IFIH1 gene such as rs1990760, which results in a non-synonymous mutation that
changes alanine at position 946 to a threonine, is highly associated with increased risk for T1D.
Studies in human PBMCs and mice have demonstrated that the A946T SNP results in an increased
sensitivity to viral ligands and subsequently a stronger downstream IFN response. Macrophages have
been shown previously to play an important role in T1D initiation, however, the response of β-cells to
viral infection is also important. Our central hypothesis is that T1D-associated SNPs result in an
exacerbated islet-resident macrophage immune response and β-cell inflammatory response following
CVB3 infection which contributes to the initiation of autoimmunity. This will be tested using monocyte-
derived macrophages and dendritic cells and induced pluripotent stem cells engineered to become
human pancreatic β-cells from healthy donors and patients with T1D that are genotyped for IFIH1
SNPs that contribute to T1D susceptibility and resistance.

## Key facts

- **NIH application ID:** 10134042
- **Project number:** 1R01DK127497-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** CLAYTON E MATHEWS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,190,423
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134042

## Citation

> US National Institutes of Health, RePORTER application 10134042, Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes (1R01DK127497-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134042. Licensed CC0.

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