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

Abstract

<p dir="ltr">Objective</p><p dir="ltr">The TrialNet Oral Insulin Prevention Trial (TN07) tested oral insulin to prevent Stage 3 type 1 diabetes in 560 Stage 1 relatives of individuals with type 1 diabetes (T1D). Of the three pre-defined risk strata, participants in Secondary Stratum 1 (SS1), characterized by low first-phase insulin release (n=55), responded significantly better to oral insulin. We aimed to identify genetic factors associated with treatment response.</p><p dir="ltr">Research Design and Methods</p><p dir="ltr">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 pre-selected T1D-associated SNPs, the T1D genetic risk score-2 (T1D-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. </p><p dir="ltr">Results</p><p dir="ltr">GLIS3 rs7020673 was significantly associated with response to oral insulin in SS1 (BH-corrected p-value=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 (HR=0.22 vs HR=1.09; unadjusted/adjusted p=0.031/0.045) 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/adjusted p=0.003/0.006) 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. </p><p dir="ltr">Conclusions</p><p dir="ltr">Genetic differences distinguish responders from non-responders to oral insulin for T1D prevention. Genetics may enable precision medicine by identifying individuals likely to benefit from T1D-modifying therapies.</p><p><br></p>

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