Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.

Summary

FI-associated variants cluster into seven mechanistic groups that differentially link to T2D and cardiovascular outcomes. Polygenic scores derived from “diabetogenic” clusters predict variable risks for CAD, MI, and stroke, with a sex-specific MI risk in the visceral adiposity cluster among men without T2D. Findings decouple elevated FI from uniform disease risk, enabling process-specific risk stratification.

Key Findings

• Seven FI-associated genetic clusters were identified with distinct mechanisms.
• Clusters split into non-diabetogenic vs. diabetogenic hyperinsulinemia.
• In >1.1M individuals, cluster-specific polygenic scores showed varying risks for CAD, MI, and stroke.
• Visceral adiposity cluster conferred a sex-specific MI risk in males without T2D.
• Processes can decouple elevated FI from T2D and cardiovascular risk.

Clinical Implications

Risk prediction and prevention strategies can incorporate cluster-specific polygenic scores and phenotypes (e.g., visceral adiposity vs. inflammation) rather than relying on fasting insulin alone.

Limitations

• Observational genetic design cannot establish causality for all pathways
• Potential heterogeneity in phenotype definitions and cohort ascertainment

Future Directions

Integrate cluster-specific PRS into clinical risk tools; test targeted interventions (e.g., adiposity vs. inflammation pathways) in precision prevention trials.