Characterizing Immunogenetics in Type 1 Diabetes

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PROJECT SUMMARY/ABSTRACT The long-term objective of our research is to learn and understand genetic mechanisms underlying initiation and progression of type 1 diabetes mellitus (T1DM), and to develop effective screening, diagnosis, preventive, and treatment strategies in the fight against T1DM. In this project, our focus is on genetic associations with the progression from seroconversion to the onset of T1DM, more specifically, discovering novel Conformational Regulatory Segments (CRS) in HLA/KIR/FcGR/IGHG genes that are responsible for the disease progression; CRS refer to both regulatory and functional elements, including peptides, nucleotides or other regulatory elements within or between genes. The HLA/KIR/FcGR/IGHG genes are highly polymorphic and Next Generation Targeted Sequencing (NGTS) will be used as extended genetic polymorphisms go under the radar of GWAS. Discovering and characterizing progression-associated CRS within HLA/KIR/FcGR/IGHG genes would help us to understand the genetic mechanism of the disease progression, and further to develop effective prevention and treatment remedies to slow or even revert progression to clinical diagnosis. In 2018, we received a bridge funding from NIDDK to carry out a pilot study of HLA genes in the disease progression, based on Diabetes Prevention Trial-1 (DPT-1). Our pilot study produced an important finding of two specific residues β57 and (-18β), within HLA-DQB1, in which β57 was structurally known to play an important role in antigen recognition and the residue (-18β) located in the signal peptide. In support of this application, we obtained clinical and genetic data from another multi-center international Oral Insulin Prevention Trial (TN07) and were able to replicate the genetic association with β57. We were able to partially replicate the association with the residue (-18β), even though DQ genotyping at intermediate resolution did not cover the residue (-18β) located in the signal peptide. To build on this preliminary result, this proposal has two specific aims: Aim 1 is to estimate the penetrance of DQB1* β57, with or without (-18β), to the progression from the precisely determined seroconversion to T1DM onset, using The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY is a prospectively conducted birth cohort and has frequent measurements of autoantibodies so that seroconversion time can be precisely determined. Aim 2 is to carry out mechanistic investigation of DQB1 CRS as well as additional CRS in HLA/KIR/ FcGR/IGHG genes, leveraging extensive functional data collected in TEDDY. Specifically, we will assess how discovered CRS associate with longitudinally measured autoantibody levels (GADA, IAA, IA-2A, ZnT8A), the β-cell function (glucose, C-peptide, OGTT) and HbA1c levels, and will investigate how CRS associate with cis- and trans-gene expressions using the longitudinal RNAseq data in a TEDDY case-control study. Results from this project will gain significant insights into genetic mechanism underlying the disease progression and will impact the translational research of preventative and therapeutic methods/strategies against T1DM.