What is the clinical evidence from this study?

Study design: Cohort. Population: Youth-onset type 2 diabetes (YT2D) (n=355). Intervention: QTL-informed molecular profiles. Primary outcome: 19 incident comorbidities (C-index >0.7).

What does this research mean for the field?

Quantitative trait loci (QTL)-informed multi-omic molecular profiles can accurately predict long-term incident comorbidities, such as rapid eGFR decline, in youth-onset type 2 diabetes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The aim is to identify molecular drivers of youth-onset type 2 diabetes for early detection and care.

June 7, 2026

2401-P: Genetic Regulation of Molecular Traits Enhances Precision Risk Stratification in Youth-Onset Type 2 Diabetes

Key Result

QTL-informed molecular profiles accurately predicted eight incident comorbidities, including rapid eGFR decline and hyperfiltration, in youth-onset type 2 diabetes (C-index >0.7).

Key Points

The aim is to identify molecular drivers of youth-onset type 2 diabetes for early detection and care.
Integrated whole-exome sequencing, proteomics, and metabolomics in 355 TODAY participants.
Colocalization with GWAS for T2D-related traits to assess shared causal variants.
Used Cox models and cross-validation predictive techniques on molecular data.
Identified 1,119 QTLs at 407 genomic loci.
Linked 528 QTLs to 19 incident outcomes, with eight comorbidities predicted accurately (C-index >0.7).
Revealed 25 YT2D-related traits sharing causal variants with QTLs, identifying key biological pathways.

Study Design

Type

Cohort (n=355)

Structured PICO

Population

355 participants with youth-onset type 2 diabetes from the TODAY study, followed for 12.4 ± 1.2 years to predict incident comorbidities using molecular data.

Outcome

19 incident comorbidities (including rapid eGFR decline and hyperfiltration)

Integration of genomics, proteomics, and metabolomics can accurately predict long-term cardiorenal and metabolic complications in youth-onset type 2 diabetes.

Main Result

Effect estimate: C-index >0.7

Abstract

Introduction and Objective: Youth-onset type 2 diabetes (YT2D) is marked by rapid progression and early cardiorenal complications. Identifying molecular drivers of YT2D is critical for early detection and precision care. We integrated genomics, proteomics and metabolomics to predict incident outcomes in the TODAY study. Methods: We integrated whole-exome sequencing with 6596 plasma proteins, 93 plasma metabolites, and 58 urine metabolites measured in 355 TODAY participants to identify quantitative trait loci (QTLs). Colocalization was performed between QTLs and GWAS (UK Biobank) for T2D-related traits to evaluate shared causal variants. Cox models identified QTLs associated with 19 incident comorbidities (follow-up 12.4 ± 1.2 yrs). We applied cross-validation to ridge regression, lasso and mboost using molecular data to predict comorbidities. Results: We identified 1,119 QTLs at 407 genomic loci. GWAS colocalization revealed 25 YT2D-related traits sharing causal variants with QTLs, highlighting biological pathways relevant to metabolic risk. Cox models linked 528 QTLs to 19 incident outcomes. Eight comorbidities were accurately predicted (C-index 0.7), including rapid eGFR decline and hyperfiltration (Fig. 1). Conclusion: QTL-informed molecular profiles reveal early signatures of metabolic risk and show strong potential for predicting long-term complications in YT2D, supporting their integration into risk stratification and prevention strategies. Disclosure M. D'Antonio: None. P. Bjornstad: Consultant; Current; Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk. Y. Choi: None. L. Pyle: None. V. Das: Employee; Current; Novo Nordisk A/S. M. Grams: Other - Received a grant from the NKF that was funded by Vertex; Ended; Vertex Pharmaceuticals Incorporated. M. Kelsey: Research Support; Current; Rhythm Pharmaceuticals, Inc. R. Nelson: None. S. Srinivasan: Research Support; Current; Abbott, Eli Lilly and Company. K. Sulek: Employee; Current; Novo Nordisk A/S. K. Kiryluk: None. J. Goodrich: None. D. Gordin: Advisory Panel; Ended; Bayer AG, Boehringer Ingelheim International GmbH. Advisory Panel; Current; AstraZeneca. Advisory Panel; Ended; Astellas Pharma Inc., GE Healthcare Systems. Speaker's Bureau; Ended; Fresenius Medical Care, Novo Nordisk, Ratiopharm. Advisory Panel; Ended; Harald AI. E.D. Nguyen: None. L.M. Laffel: Other - Travel support for scientific presentations; Ended; Boehringer Ingelheim International GmbH. Other - DSMB Chair; Ended; Janssen Pharmaceuticals, Inc. Consultant; Current; Dexcom, Inc. Advisory Panel; Current; Medtronic, Sequel, Tandem Diabetes Care, Inc. Consultant; Current; Roche Diabetes Care, Sinocare. Advisory Panel; Ended; Sanofi. Advisory Panel; Current; MannKind Corporation. J.M. Forbes: None. H. Hampson: None. S. Ramesh: None. J.D. Weissenkampen: None. P. Narongkiatikhun: None. K. Tommerdahl: Advisory Panel; Current; Sanofi. J. Cole: None. A. Karihaloo: None. S.L. Leidholt: None. Funding American Diabetes Association (7-23-ICTST2DY-08), NIH/NIDDK (U01 DK61242, U01 DK072493, UM1 DK072493)NIH/NCATS (UL1 TR000077, UL1 TR000114)

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