Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes
Abstract 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 clu...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57452-y |
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| author | Magdalena Sevilla-González Kirk Smith Ningyuan Wang Aubrey E. Jensen Elizabeth M. Litkowski Hyunkyung Kim Daniel A. DiCorpo Sarah Hsu Jinrui Cui Ching-Ti Liu Chenglong Yu John J. McNeil Paul Lacaze Kenneth E. Westerman Kyong-Mi Chang Philip S. Tsao Lawrence S. Phillips Mark O. Goodarzi Rob Sladek Jerome I. Rotter Josée Dupuis Jose C. Florez Jordi Merino James B. Meigs Jin J. Zhou Sridharan Raghavan Miriam S. Udler Alisa K. Manning |
| author_facet | Magdalena Sevilla-González Kirk Smith Ningyuan Wang Aubrey E. Jensen Elizabeth M. Litkowski Hyunkyung Kim Daniel A. DiCorpo Sarah Hsu Jinrui Cui Ching-Ti Liu Chenglong Yu John J. McNeil Paul Lacaze Kenneth E. Westerman Kyong-Mi Chang Philip S. Tsao Lawrence S. Phillips Mark O. Goodarzi Rob Sladek Jerome I. Rotter Josée Dupuis Jose C. Florez Jordi Merino James B. Meigs Jin J. Zhou Sridharan Raghavan Miriam S. Udler Alisa K. Manning |
| author_sort | Magdalena Sevilla-González |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-bbb608eff5e445b9b31be9cf6fddb381 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bbb608eff5e445b9b31be9cf6fddb3812025-08-20T02:56:11ZengNature PortfolioNature Communications2041-17232025-03-0116111210.1038/s41467-025-57452-yHeterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomesMagdalena Sevilla-González0Kirk Smith1Ningyuan Wang2Aubrey E. Jensen3Elizabeth M. Litkowski4Hyunkyung Kim5Daniel A. DiCorpo6Sarah Hsu7Jinrui Cui8Ching-Ti Liu9Chenglong Yu10John J. McNeil11Paul Lacaze12Kenneth E. Westerman13Kyong-Mi Chang14Philip S. Tsao15Lawrence S. Phillips16Mark O. Goodarzi17Rob Sladek18Jerome I. Rotter19Josée Dupuis20Jose C. Florez21Jordi Merino22James B. Meigs23Jin J. Zhou24Sridharan Raghavan25Miriam S. Udler26Alisa K. Manning27Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General HospitalPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and HarvardDepartment of Biostatistics, Boston University School of Public HealthPhoenix Veterans Affairs Medical CenterVeterans Affairs Eastern Colorado Health Care SystemPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and HarvardDepartment of Biostatistics, Boston University School of Public HealthPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and HarvardDivision of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical CenterDepartment of Biostatistics, Boston University School of Public HealthSchool of Public Health and Preventive Medicine, Monash UniversitySchool of Public Health and Preventive Medicine, Monash UniversitySchool of Public Health and Preventive Medicine, Monash UniversityClinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General HospitalCorporal Michael J Crescenz VA Medical CenterVeterans Affairs Palo Alto Health Care SystemAtlanta VA Medical CenterDivision of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical CenterDepartment of Human Genetics and Department of Medicine, McGill UniversityThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Biostatistics, Boston University School of Public HealthDepartment of Medicine, Harvard Medical SchoolPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and HarvardDepartment of Medicine, Harvard Medical SchoolPhoenix Veterans Affairs Medical CenterVeterans Affairs Eastern Colorado Health Care SystemDepartment of Medicine, Harvard Medical SchoolClinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General HospitalAbstract 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.https://doi.org/10.1038/s41467-025-57452-y |
| spellingShingle | Magdalena Sevilla-González Kirk Smith Ningyuan Wang Aubrey E. Jensen Elizabeth M. Litkowski Hyunkyung Kim Daniel A. DiCorpo Sarah Hsu Jinrui Cui Ching-Ti Liu Chenglong Yu John J. McNeil Paul Lacaze Kenneth E. Westerman Kyong-Mi Chang Philip S. Tsao Lawrence S. Phillips Mark O. Goodarzi Rob Sladek Jerome I. Rotter Josée Dupuis Jose C. Florez Jordi Merino James B. Meigs Jin J. Zhou Sridharan Raghavan Miriam S. Udler Alisa K. Manning Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes Nature Communications |
| title | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| title_full | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| title_fullStr | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| title_full_unstemmed | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| title_short | Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| title_sort | heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes |
| url | https://doi.org/10.1038/s41467-025-57452-y |
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