Introduction

Type 1 diabetes (T1D) progresses through presymptomatic stages characterized by islet autoimmunity and subsequent dysglycemia, with substantial interindividual variability in progression rate and beta cell decline⁽¹⁾. This heterogeneity likely contributes to differential responses to immunomodulatory and antigen-specific therapies, particularly in prevention and recent-onset trials⁽²⁾.

Genetic susceptibility is dominated by human leukocyte antigen (HLA) class II haplotypes, notably DR3-DQ2 and DR4-DQ8, and complemented by non-HLA loci influencing immune regulation, antigen tolerance, and beta cell biology⁽³⁾. These determinants provide a biologically grounded framework for therapeutic stratification.

A conceptual distinction is necessary between genetic response markers and genetic eligibility criteria. Genetic response markers are typically identified through treatment × genotype interaction analyses and generate hypotheses regarding differential benefit or potential harm. Genetic eligibility criteria represent prospective operational decisions restricting enrollment based on sufficiently robust and validated evidence. Translation from response marker to eligibility criterion generally follows a staged pathway, from prospective stratification to genetic enrichment and ultimately, genotype-restricted trial design when supported by consistent mechanistic and clinical validation.

Methods

A narrative review was conducted of interventional clinical trials in T1D, including primary prevention, secondary prevention (stage 1 or stage 2), and recent-onset disease (stage 3). Trials were included if genetics was explicitly used as a criterion for inclusion or enrichment, or if treatment × genotype interactions were reported in primary publications or associated analyses. Observational studies were excluded.

Priority was given to trials with documented genetic eligibility criteria, predefined genetic stratification, or formal statistical testing of treatment×genotype interactions. Trials using explicit genetic eligibility criteria are summarized in table 1, and trials reporting genetic modifiers of therapeutic response are summarized in table 2.

Results

Primary prevention

The Primary Oral Insulin Trial (POInT) evaluated highdose daily oral insulin in infants selected for elevated genetic risk of islet autoimmunity⁽⁴⁾. Genetic screening was integral to trial design, increasing event rates and statistical efficiency (Table 1). Although the composite primary endpoint of multiple islet autoantibodies or T1D was not reduced overall, POInT reported a treatment×genotype interaction at INS rs1004446⁴ (Table 2). Signals suggested benefit in genetically susceptible INS genotypes and potential adverse signals in non-susceptible genotypes for selected outcomes.

Other primary prevention trials, including rial to Reduce Insulin-Dependent Diabetes Mellitus in the Genetically at Risk (TRIGR)⁽⁵⁾, Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes (FINDIA)⁽⁶⁾, and BABYDIET⁽⁷⁾, incorporated HLA-based eligibility criteria and are summarized in table 1. Although these were dietary interventions rather than classical immunotherapies, they demonstrate operational use of genetic selection in interventional prevention. The Type 1 Diabetes Prediction and Prevention Study (DIPP) nasal insulin trial similarly incorporated HLA-based eligibility with autoantibody positivity⁽⁸⁾ (Table 1).

Secondary prevention (stage 1)

The TrialNet Oral Insulin Prevention Trial (TN07) evaluated 7.5 mg/day oral insulin in autoantibodypositive relatives⁽⁹⁾. The overall trial did not demonstrate significant benefit. However, a pharmacogenetic analysis examined genetic modifiers of response within a predefined metabolic risk stratum characterized by reduced first-phase insulin response⁽¹⁰⁾ (Table 2).

Within this metabolically enriched subgroup, GLIS3 rs7020673 was significantly associated with therapeutic response after correction for multiple testing⁽¹⁰⁾. A specific HLA-DR4 haplotype showed nominal association. Exploratory analyses also suggested that T1D genetic risk score 2 (T1DGRS2) and type 2 diabetes polygenic risk scores were associated with magnitude of benefit in defined subgroups⁽¹⁰⁾ (Table 2). A complementary reanalysis focusing on HLA-DR4-DQ8 and elevated insulinomaassociated protein 2 autoantibodies (IA-2A) reported signals of delayed progression in a defined subgroup⁽¹¹⁾ (Table 2). These findings indicate that pharmacogenetic signals may be more detectable when combined with clinical or metabolic enrichment and suggest that distinct genetic axes, including autoimmune risk, beta cell biology, and metabolic traits, may modulate preventive immunotherapy response.

Stage 2 prevention

Teplizumab, an anti-CD3 monoclonal antibody, delayed progression to clinical T1D in high-risk relatives with stage 2 disease⁽¹²⁾. Exploratory subgroup analyses suggested greater efficacy among HLADR3–negative and HLA-DR4–positive participants⁽¹²⁾ (Table 2). Although hypothesis-generating, this represents one of the clearest examples of potential HLA-modulated efficacy in a non–antigen-specific immunotherapy.

Recent-onset (stage 3) T1D

Genetic restriction has been more explicitly implemented in antigen-specific strategies. DIAGNODE-3 (a phase 3 trial of intralymphatic glutamic acid decarboxylase[GAD]–alum immunotherapy in recent-onset type 1 diabetes) restricts enrollment to individuals with HLA-DR3-DQ2 for intralymphatic GAD–alum immunotherapy plus vitamin D⁽¹³⁾ (Table 1). This design reflects translation from response marker to eligibility restriction within a precision-medicine framework. In contrast, most recent-onset trials of non–antigen-specific therapies have not routinely incorporated germline pharmacogenetics as primary modifiers of efficacy in main publications.

Conclusions

Genetics is already integrated into T1D prevention trial design and, in selected cases, into recent-onset disease. Trials using explicit genetic eligibility criteria are summarized in table 1, and trials reporting genetic modifiers of therapeutic response are summarized in table 2. POInT demonstrates genetic risk enrichment and suggests genotype-dependent heterogeneity of oral insulin response at the INS locus⁽⁴⁾. TN07 pharmacogenetic analyses implicate GLIS3 variants, specific HLA haplotypes, and polygenic risk scores in modulating response within metabolically enriched subgroups⁽¹⁰⁾. Teplizumab provides proof-of-concept for stage 2 prevention with exploratory evidence of HLA-modulated heterogeneity⁽¹²⁾.

Collectively, these findings support prospective validation of genetic treatment-response interactions and their disciplined translation into trial design to advance biologically stratified immunotherapy in T1D.

Acknowledgements

MJR was funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK121843).

Conflicts of interest

MJR received honoraria from Lilly, Sanofi, MedLearn and NIDDK.

1. Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015; 38: 1964-74.
2. Felton JL, Griffin KJ, Oram RA, Speake C, Long SA, Onengut-Gumuscu S, et al. Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review. Commun Med 2023; 3: 130.
3. Redondo MJ, Onengut-Gumuscu S, Gaulton KJ. Genetics of type 1 diabetes. In Lawrence JM, Casagrande SS, Herman WH, Wexler DJ, Cefalu WT, eds. Diabetes in America. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); 2023. URL: http: //www.ncbi.nlm.nih.gov/books/ NBK597411/. Accessed February 11, 2026.
4. Ziegler AG, Achenbach P, Weiß A, Berner R, Casteels K, Elding Larsson H, et al. Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial. Lancet 2025; 406: 2564-76.
5. Writing Group for the TRIGR Study Group, Knip M, Åkerblom HK, Al Taji E, Becker D, Bruining J, Castano L, et al. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. JAMA 2018; 319: 38-48.
6. Vaarala O, Ilonen J, Ruohtula T, Pesola J, Virtanen SM, Härkönen T, et al. Removal of bovine insulin from cow’s milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study. Arch Pediatr Adolesc Med 2012; 166: 608-14.
7. Hummel S, Pflüger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 2011; 34: 1301-5.
8. Näntö-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 2008; 372: 1746-55.
9. Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group, Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA 2017; 318: 1891-902.

10. You L, Parikh HM, Triolo TM, Ferrat LA, Templeman EL, Oram RA, et al. Genetic predictors of response to oral insulin for type 1 diabetes prevention. Diabetes Care 2026; 49: 344-51.

11. Zhao LP, Papadopoulos GK, Skyler JS, Parikh HM, Kwok WW, Bondinas GP, et al. Oral insulin delay of stage 3 type 1 diabetes revisited in HLA DR4-DQ8 participants in the TrialNet Oral Insulin Prevention Trial (TN07). Diabetes Care 2024; 47: 1608-16.

12. Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 2019; 381: 603-13.

13. Ludvigsson J, Eriksson L, Nowak C, Teixeira PF, Widman M, Lindqvist A, et al. Phase III, randomised, double-blind, placebo-controlled, multicentre trial to evaluate the efficacy and safety of rhGAD65 to preserve endogenous beta cell function in adolescents and adults with recently diagnosed type 1 diabetes, carrying the genetic HLA DR3-DQ2 haplotype: the DIAGNODE-3 study protocol. BMJ Open 2022; 12: e061776.