2025/12/09 by Lu You, Hemang Parikh, Taylor M. Triolo +9 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Diabetes and associated disorders #Pancreatic function and diabetes #Diabetes Management and Research
paper · pdf · doi:10.2337/dc25-2006
openalex publication_date 2025/12/09 · openalex created_date 2025/12/10 · openalex updated_date 2026/08/01
OBJECTIVE: The TrialNet Oral Insulin Prevention Trial TN07 tested oral insulin to prevent stage 3 type 1 diabetes (T1D) in 560 relatives with stage 1 T1D of individuals with T1D. Of the three predefined risk strata, participants in secondary stratum 1 (SS1) (n = 55), characterized by low first-phase insulin release, responded significantly better to oral insulin. We aimed to identify genetic factors associated with treatment response. RESEARCH DESIGN AND METHODS: The TEDDY-T1DExomeChip was used to genotype 552 participants with available DNA. Cox models examined associations between response to oral insulin and HLA haplotypes, 33 preselected T1D-associated single nucleotide polymorphisms, T1D genetic risk score 2 (GRS2), and type 2 diabetes (T2D)-associated polygenic scores. For primary analyses, P values were Benjamini-Hochberg (BH) corrected for multiple comparisons; results not passing correction were considered nominal. RESULTS: GLIS3 rs7020673 was significantly associated with response to oral insulin in SS1 (BH-corrected P = 0.031 without and P = 0.022 with covariate adjustment). Additional nominal associations included better response with HLA-DRB1*04:01-DQA1*03:01-DQB1*03:02 (hazard ratio [HR] 0.22 vs. 1.09; unadjusted P = 0.031; adjusted P = 0.045) in SS1 and worse responses with TNFAIP3 and CTLA4 in at least one stratum. In exploratory analyses, participants with T1D-GRS2 >12.5 responded better to oral insulin (HR 0.68) than those with T1D-GRS2 ≤12.5 (HR 2.10; unadjusted P = 0.003; adjusted P = 0.006) in the overall cohort, and lower proinsulin- and obesity-partitioned T2D polygenic scores were associated with greater treatment benefit in SS1 and in another secondary stratum, respectively. CONCLUSIONS: Genetic differences distinguish responders from nonresponders to oral insulin for T1D prevention. Genetics may enable precision medicine by identifying individuals likely to benefit from T1D-modifying therapies.