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

• Published in: Human immunology Vol. 71; no. 11; pp. 1128 - 1134
• Main Authors: Chistiakov, Dimitry A., Voronova, Natalia V., Savost'Anov, Kirill V., Turakulov, Rustam I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2010
• Subjects: Adolescent; Adult; Age of Onset; Allergy and Immunology; Child; DEAD-box RNA Helicases - genetics; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Disease Progression; Enteroviral infection; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; IFIH1; Interferon-beta - biosynthesis; Interferon-beta - genetics; Interferon-Induced Helicase, IFIH1; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Lymphocyte Activation - genetics; Male; MDA5; Mutation - genetics; Poly I-C - immunology; Poly I-C - metabolism; Polymorphism; Polymorphism, Genetic; Risk; Russia; Type 1 diabetes; IFIH1; Type 1 diabetes; Enteroviral infection; MDA5; Polymorphism
• ISSN: 0198-8859; 1879-1166; 1879-1166
• DOI: 10.1016/j.humimm.2010.08.005

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.