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Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

Abstract

Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system’s interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs’ effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.

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Acknowledgments

This work was supported by National Institutes of Health Grant PO1 A142288.

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Benjamin M. Looney, Chang-Qing Xia, Patrick Concannon, David A. Ostrov, and Michael J. Clare-Salzler declare they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Michael J. Clare-Salzler.

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This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

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Looney, B.M., Xia, CQ., Concannon, P. et al. Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression. Curr Diab Rep 15, 96 (2015). https://doi.org/10.1007/s11892-015-0656-8

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  • DOI: https://doi.org/10.1007/s11892-015-0656-8

Keywords

  • IFIH1/melanoma differentiation-associated protein 5/MDA5
  • rs1990760/A946T
  • rs3747517/R843H
  • rs35667974/I923V
  • Type I interferon