title: Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients.
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 (T1D) 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% CI, 0.30-0.66, p = 5.4 × 10(-5)). We detected a 3.5-fold greater frequency of enteroviral RNA in T1D subjects compared with controls (p <1.0 × 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 × 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-β in PMBCs compared with the other IFIH1 variants. The upregulated MDA5-dependent production of inflammatory cytokines could enhance the autoimmune destruction of β-cells mediated by self-reactive T-cells.
authors.affiliation: Department of Molecular Diagnostics, National Research Center, Moscow, Russia. dimitry.chistiakov@lycos.com
authors.forename: Dimitry A
authors.initials: DA
authors.lastname: Chistiakov
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Voronova
authors.forename: Kirill V
authors.initials: KV
authors.lastname: Savost'Anov
authors.forename: Rustam I
authors.initials: RI
authors.lastname: Turakulov
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D011070:Poly I-C / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D012306:Risk; D012426:Russia
chemical_list: D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C