Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes
Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.
Authors
- Paul Lacaze (ORCID: https://orcid.org/0000-0002-0902-6798)
- Robert Sladek (ORCID: https://orcid.org/0000-0002-2730-1204)
- Magdalena Sevilla-González (ORCID: https://orcid.org/0000-0001-6135-9998)
- Sridharan Raghavan (ORCID: https://orcid.org/0000-0003-0643-4873)
- Mark O. Goodarzi (ORCID: https://orcid.org/0000-0001-6364-5103)
- Chenglong Yu (ORCID: https://orcid.org/0000-0002-0546-2779)
- N. Wang (ORCID: https://orcid.org/0009-0002-2192-5566)
- James B. Meigs (ORCID: https://orcid.org/0000-0002-2439-2657)
- Alisa K. Manning (ORCID: https://orcid.org/0000-0003-0247-902X)
- Jinrui Cui
- Kyong‐Mi Chang (ORCID: https://orcid.org/0000-0001-6811-9364)
- Jordi Merino (ORCID: https://orcid.org/0000-0001-8312-1438)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Kenneth E. Westerman (ORCID: https://orcid.org/0000-0001-7619-1868)
- Sarah Hsu (ORCID: https://orcid.org/0000-0001-9823-9711)
- José C. Florez (ORCID: https://orcid.org/0000-0002-1730-9325)
- Elizabeth Litkowski (ORCID: https://orcid.org/0000-0002-7079-696X)
- Hyunkyung Kim (ORCID: https://orcid.org/0000-0001-7964-3073)
- Josée Dupuis (ORCID: https://orcid.org/0000-0003-2871-3603)
- A. E. Jensen (ORCID: https://orcid.org/0000-0001-8807-428X)
- John J. McNeil (ORCID: https://orcid.org/0000-0002-1049-5129)
- Philip S. Tsao (ORCID: https://orcid.org/0000-0001-7274-9318)
- Daniel DiCorpo (ORCID: https://orcid.org/0000-0001-8550-8214)
- Lawrence S. Phillips (ORCID: https://orcid.org/0000-0002-6542-8046)
- Miriam S. Udler (ORCID: https://orcid.org/0000-0003-3824-9162)
- Kirk Smith (ORCID: https://orcid.org/0000-0002-4338-4812)
- Ching‐Ti Liu (ORCID: https://orcid.org/0000-0002-0703-0742)
- Jin Zhou (ORCID: https://orcid.org/0000-0001-7983-0274)
Institutions
- Broad Institute (US)
- Boston University (US)
- University of Copenhagen (DK)
- Cedars-Sinai Medical Center (US)
- Harvard University (US)
- VA Palo Alto Health Care System (US)
- UCLA Health (US)
- Novo Nordisk Foundation (DK)
- UCLA Medical Center (US)
- Massachusetts General Hospital (US)
- Philadelphia VA Medical Center (US)
- VA Eastern Colorado Health Care System (US)
- Atlanta VA Medical Center (US)
- Center for Systems Biology (US)
- Harbor–UCLA Medical Center (US)
- McGill University (CA)
- University of Colorado Anschutz Medical Campus (US)
- Monash University (AU)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-15
- DOI
- https://doi.org/10.1038/s41467-025-57452-y
- Citations
- 9
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 16.36
Funders
- U.S. Department of Defense
- American Diabetes Association
- Boettcher Foundation
- Office of Research and Development
- Monash University
- Menzies Institute for Medical Research
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences
- Congressionally Directed Medical Research Programs