Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-beta production in peripheral blood mononuclear cells of type 1 diabetes patients

Chistiakov, DA; Voronova, NV; Savost&#39;anov, KV; Turakulov, RI

Author(s): Chistiakov, DA; Voronova, NV; Savost'anov, KV; Turakulov, RI;
Details: Publication Year 2010-11,Volume 71,Issue #11,Page 1128-1134
Journal Title: HUMAN IMMUNOLOGY
Publication Type: Journal Article
Abstract: Melanoma differentiation-associated 5 (MDA5), a product of the IFIH1 gene, is responsible for sensing double-stranded viral double-stranded RNA (RNA). In this study, we showed a significant association of two rare IFIH1 variants, rs35744605 (E627X) and rs35667974 (I923V), with decreased risk of type 1 diabetes (T1 D) in a Russian population (for the allele X627, odds ratio [OR] = 0.39, 95% confidence interval [95% CI] = 0.22-0.69, p = 0.0015; for the allele V923, OR = 0.45, 95% Cl, 0.30 - 0.66, p = 5.4 x 10(-5)). We detected a 3.5-fold greater frequency of enteroviral RNA in T1 D subjects compared with controls (p < 1.0 x 10(-8)), and 2.1-fold more frequent presence of viral RNA in T1D patients with a recent-onset diabetes (duration <= 1 year) compared with those with a longer disease (p < 1.0 x 10(-8)). The carriage of the predisposing IFIH1 EI/EI haplogenotype was significantly associated with a 1.5- to 1.7-fold increase in the poly(I:C)-stimulated secretion of IFN-beta in PMBCs compared with the other IFIH1 variants. The upregulated MDA5-dependent production of inflammatory cytokines could enhance the autoimmune destruction of p-cells mediated by self-reactive T-cells. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Publisher: ELSEVIER SCIENCE INC
Keywords: DOUBLE-STRANDED-RNA; GENOME-WIDE ASSOCIATION; ENTEROVIRUS RNA; RIG-I; INNATE IMMUNITY; DENDRITIC CELLS; VIRUS-INFECTION; RISK-FACTOR; RESPONSES; MDA5
Publisher's Version: https://doi.org/10.1016/j.humimm.2010.08.005
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Creation Date: 2010-11-01 12:00:00