# Whole blood gene expression to identify biomarkers of disease risk, progression and response to therapy in Type 1 diabetes

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $432,984

## Abstract

Summary
 In this grant, we propose to perform gene expression analysis on peripheral blood cells
(PBC) of auto-antibody negative first degree relatives of T1D patients (AA- FDRs) and AA+
FDRs who have either progressed (progressors) or not progressed to hyperglycemia (non-
progressors), compared to healthy non-T1D related controls. We will also perform gene
expression analysis on PBCs of patients enrolled in the TrialNet Abatacept (CTLA4-Ig) New
Onset Study (TN-09). The proposed studies will confirm and extend our work on the
identification of whole blood biomarkers of disease susceptibility and disease progression in
T1D, and initiate our studies on biomarkers of response to therapy.
 Preliminary data generated under funding from the JDRF suggests that the PBC gene
expression profiles of T1D and T1D-related individuals are more similar to each other than to
healthy normal non-diabetes-related controls; that is, there is a prodromal gene expression
signature that can identify disease risk in the PBCs of AA- FDRs of T1D patients who show no
clinical signs of disease. Based on these preliminary data, we hypothesize that families of T1D
patients, all have an environmentally-driven, epigenetically-controlled gene expression signature
of risk that can be seen in peripheral blood. We identified a subset of AA- FDRs that had
elevated levels of interferon-induced gene expression in their PBCs. These individuals also
expressed a gene expression signature that was more similar to AA+ FDRs who progressed to
hyperglycemia than to AA+ FDRs who did not progress, or to other AA- FDRs, and to controls,
suggesting that whole blood gene expression biomarkers could be used to identify individuals
who will progress to hyperglycemia prior to seroconversion. In patients who seroconverted
(AA+), we found that gene expression was most changed during the early stages of disease (>3
years before the onset of hyperglycemia) in progressors compared to non-progressors. This
indicates that we might be able to identify biomarkers that not only distinguish AA+ progressors
from AA+ non-progressors, but also predict the rate of disease progression. Finally, studies
have shown that PBC gene expression signatures differ in recent onset hyperglycemic patients
that responded to anti-CD3 therapy compared to those who did not respond (AbATE trial). We
hypothesize that we may also see a difference in gene expression in patients who respond to
CTA4-Ig (Abatacept) compared to those who do not respond, 3 months after the initiation of
therapy (TN-09). If non-responders could be identified early, this would allow time for other
therapies to be tested before total loss of beta cell mass/function occurs.
 Three specific aims are proposed. The first specific aim is to validate the prodromal
gene expression pattern seen in diabetes related AA- individuals. The second specific aim is
to identify both a PBC gene expression signature of T1D disease progression (identifying those
who will progress ...

## Key facts

- **NIH application ID:** 9918349
- **Project number:** 5R01DK115874-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** CHARLES GARRISON FATHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,984
- **Award type:** 5
- **Project period:** 2018-04-10 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918349

## Citation

> US National Institutes of Health, RePORTER application 9918349, Whole blood gene expression to identify biomarkers of disease risk, progression and response to therapy in Type 1 diabetes (5R01DK115874-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918349. Licensed CC0.

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