{"doi":"10.2337/dc25-2006","title":"Genetic Predictors of Response to Oral Insulin for Type 1 Diabetes Prevention","abstract":"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.","journal":"Diabetes Care","year":2025,"id":584752,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5962,"name":"Hemang Parikh","orcid":"0000-0002-9076-6709","position":1,"is_corresponding":false},{"id":533259,"name":"Taylor M. Triolo","orcid":"0000-0003-4796-6542","position":2,"is_corresponding":false},{"id":25375,"name":"Lauric Ferrat","orcid":"0000-0002-3166-9685","position":3,"is_corresponding":false},{"id":1369636,"name":"Erin L. Templeman","orcid":"0009-0007-4306-7909","position":4,"is_corresponding":false},{"id":249639,"name":"Richard A. Oram","orcid":"0000-0003-3581-8980","position":5,"is_corresponding":false},{"id":336608,"name":"Peter A. Gottlieb","orcid":"0000-0002-7601-8536","position":6,"is_corresponding":false},{"id":11274,"name":"Stephen S. Rich","orcid":"0000-0003-3872-7793","position":7,"is_corresponding":false},{"id":428049,"name":"Suna Önengüt-Gümüşcü","orcid":"0000-0002-6563-8334","position":8,"is_corresponding":false},{"id":96015,"name":"Andrea K. Steck","orcid":"0000-0002-5931-9484","position":9,"is_corresponding":false},{"id":5970,"name":"Jeffrey P. Krischer","orcid":"0000-0003-4526-888X","position":10,"is_corresponding":false},{"id":7390,"name":"María J. Redondo","orcid":"0000-0001-5871-4645","position":11,"is_corresponding":false},{"id":787689,"name":"Lu You","orcid":"0000-0002-9400-2060","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41364459","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}