An integrated strategy to define the functional and synergistic impact of T1D causal variants

Seattle Children'S Hospital, Seattle WA

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Type 1 diabetes (T1D) is a complex disease arising as a result of both genetic background and environmental exposures. Multiple biochemical and developmental programs have been implicated in its pathogenesis. While rare single gene defects can result in T1D, we hypothesize that T1D generally arises through a combination of synergistic defects in two or more key immune ?programs?. Genetic variants associated with T1D can be used as a guide to understand how alterations in these programs individually and in combination contribute to the development and progression of T1D. Although multiple programs are implicated in T1D, in this grant we will focus on four coding variants, PTPN22, TYK2, SH2B3 and IFIH1. Our work and others has established that: the TID PTPN22 risk variant (PTPN22R) alters antigen receptor (AR) signaling, impacting T cell selection, development and survival; the TYK2 protective variant (TYK2P) and SH2B3 risk variant (SH2B3R) alter cytokine responses; and the IFIH1 risk variant (IFIH1R) results in enhanced IFN-1 production. In this DP3, we will address the hypothesis that PTPN22R, TYK2NP, SH2B3R variants individually and in combination contribute to the development of pathogenic islet specific T cells in T1D; and that the impact of these variants is further amplified by an enhanced Interferon response, as seen with IFIH1R, resulting in increased risk for disease development. We propose the following specific aims: Aim 1 will determine how the altered AR signaling program associated with PTPN22R leads to increased pathogenicity of islet specific effector T cells; Aim 2 will determine how SH2B3R and TYK2P contribute to alterations in the T cell activation and differentiation program in health and disease; and Aim 3 will determine whether PTPN22R synergizes with signaling programs impacted by SH2B3R, TYK2P or IFIH1R to modulate immune tolerance and T1D development. We will apply an integrated approach utilizing: primary human cells, murine models of the human risk variant, and by taking advantage of cutting edge gene editing and proteomics technologies. This approach will allow us to comprehensively interrogate the functional implications of these specific genes and, how the signaling programs that they modulate, function in concert to contribute to TID. Notably, we have found that the altered programs driven by T1D risk variants often mimic those observed in disease, even in patients lacking the specific risk variants we model. Thus, studies of specific genetic risk variants and their functional implications are broadly applicable to understanding the pathogenesis of T1D and will inform the development of new biomarkers and therapeutic agents to treat type 1 diabetes.