154-OR: Genetic Predictors of Response to Oral Insulin for Type 1 Diabetes Prevention
Authors: YOU LU , PARIKH HEMANG M. , TRIOLO TAYLOR M. , FERRAT LAURIC A. , TEMPLEMAN ERIN , ORAM RICHARD A. , GOTTLIEB PETER , RICH STEPHEN S. , ONENGUT-GUMUSCU SUNA , STECK ANDREA , KRISCHER JEFFREY , REDONDO MARIA J. 
Published: June 2024

Introduction: TrialNet TN07, a randomized controlled trial, assessed oral insulin for preventing type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. Of 560 participants, the stratum characterized by low first-phase insulin release (LFIR) (n=57) showed a positive response to oral insulin, while others (n=503) did not. We aimed to understand genetic differences between participants with and without LFIR, and between responders and non-responders to oral insulin in the LFIR stratum.
Methods: 552 participants were genotyped using the TEDDY T1DExome array. We compared T1D and insulin associated single nucleotide polymorphisms (SNPs), human leukocyte antigen (HLA) alleles, and T1D genetic risk scores (T1DGRS) in the LFIR stratum vs others using Fisher's tests and t tests. In the LFIR stratum, we used Cox models to examine genetic factors that identify participants with slower T1D progression in response to treatment.
Results: Participants with LFIR had higher T1DGRS than those without LFIR (mean 14.2 vs 13.7, p=0.04); higher frequencies of INS rs1004446 susceptible allele (63% vs 48%, p=0.04), higher frequencies of homozygosity for IL27 rs4788084 susceptible allele (18% vs 7%, p=0.04), and lower frequencies of the HLA DRB1*13/DQA1*01 protective haplotype (5% vs 17%, p=0.02). In participants with LFIR, hazard ratio (HR) of response to oral insulin treatment compared to placebo was different in participants with vs without GLIS3 rs7020673 protective allele (respectively, HR: 0.90 vs 0.08, p=0.003), with vs without PXK/PDHB rs11705721 susceptible allele (HR: 0.26 vs 1.09, p=0.05) and with vs without the HLA DRB1*0401/DQA1*0301 susceptible haplotype (HR: 0.23 vs 1.36, p=0.01).
Conclusion: Genetic differences exist in autoantibody-positive relatives with and without LFIR, and in LFIR stratum, between responders and non-responders to oral insulin for T1D prevention. Genetics may help precision medicine by identifying candidates responsive to T1D-modifying therapies.

Disclosure
L. You: None. H.M. Parikh: None. T.M. Triolo: None. L.A. Ferrat: Consultant; Johnson & Johnson Medical Devices Companies. E. Templeman: None. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. P. Gottlieb: Other Relationship; IM Therapeutics. Research Support; Imcyse. Advisory Panel; Imcyse. Consultant; Juvenile Diabetes Research Foundation (JDRF). Research Support; Hemsley Charitable Trust, Novartis AG, Provention Bio, Inc., Precigen, Inc. Advisory Panel; ViaCyte, Inc. Research Support; Nova Pharmaceuticals. S.S. Rich: None. S. Onengut-Gumuscu: None. A. Steck: None. J. Krischer: None. M.J. Redondo: None.

Funding
This research was funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121843). The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, UC4DK117009, and the JDRF.