# Characterizing Immunogenetics in Type 1 Diabetes

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $549,316

## Abstract

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 insight...

## Key facts

- **NIH application ID:** 10811748
- **Project number:** 5R01DK132406-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** DANIEL E. GERAGHTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $549,316
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811748

## Citation

> US National Institutes of Health, RePORTER application 10811748, Characterizing Immunogenetics in Type 1 Diabetes (5R01DK132406-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10811748. Licensed CC0.

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