Genetic Predictors of Response to Oral Insulin for Type 1 Diabetes Prevention.

Abstract

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. 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. 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. 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.