Subtyping of Type 1 Diabetes as Classified by Anti-GAD Antibody, IgE Levels, and Tyrosine kinase 2 ( TYK2 ) Promoter Variant in the Japanese

Abstract

ObjectiveType 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance.Research Design and MethodsWe assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese.ResultsT1D patients had elevated IgE (median, 56.7 U/ml; p < 0.0001) compared with T2D patients (22.5 U/ml) and controls (43.3 U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03–6.97; p = 0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27–4.35; p = 0.003).InterpretationAnti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.

Diabetes, the TYK2 Gene and the Interferon Response: In Search for Environmental Causes

“…Taken together, the new findings imply that individuals carrying TYK2 variants may be a target of slowly-acting pancreotropic viruses due to their dampened IFN response ( Genoni et al, 2017 ; Mine et al, 2017 ). The results could also be of therapeutic value, as inhibitors of JAK kinases (including TYK2) are potentially valuable in autoimmune disease ( Roskoski, 2016 ), in which we would aim for protection from autoimmunity without inducing immunodeficiency.…”

“…This Commentary discusses the characteristics of autoimmune T1DM that illustrate the heterogeneity of the disease. In this issue of EBiomedicine, Mine and co-authors ( Mine et al, 2017 ) report that many Japanese patients present with T1DM in adult life and show evidence of both an autoimmune and an autoinflammatory disease. Strikingly, they detected a diabetes subtype (35% of their cohort) with neither of these features, yet enriched for a variant of the TYK2 gene encoding tyrosine kinase 2, a member of the Janus family kinases that mediates signalling for type-I interferons (IFN) and type-III IFN (also called IFN lambda; IFNL).…”

“…The study of Japanese adult-onset diabetes cases ( Mine et al, 2017 ) implicates some role for viruses, supported by the increased frequency of mild respiratory infections before diagnosis. Furthermore, given that respiratory viral infections and variants of the IFIH1 gene (interferon induced with helicase C domain 1) predispose to childhood-onset T1DM ( Gorman et al, 2017 ), it follows that viral infections may contribute to T1DM across a wide age-range.…”

“…Shortly thereafter, they also associated TYK2 promoter variants with human diabetes. It is possible, therefore, that the TYK2 variant enriched in the subgroup of insulin-dependent Japanese patients could increase susceptibility to infection and, consequently, to diabetes ( Mine et al, 2017 ; Kreins et al, 2015 ).…”

TYK2 in Tumor Immunosurveillance

“…Additionally, spontaneously mutated mouse strains have been discovered that carry mutations causing TYK2 deficiency: the B10.D1-H2 q /SgJ mouse strain harbors an amino acid exchange (TYK2 E775K ) that destabilizes the protein [68], while the SWR/J or SJL/J strains harbor Tyk2 promoter mutations that reduce TYK2 levels to below the limit of biochemical detection [69]. TYK2 promoter variants in men are associated with an increased risk of virus-induced diabetes [70,71]. The first report of an inborn missense mutation leading to loss of TYK2 in a human patient stems from 2006; since then a further nine patients with complete loss of TYK2 have been reported [42,43,72,73].…”