Evidence map›Paper›PMID 41358287›Full record

ArticlemedRxiv : the preprint server for health sciences2025

Dissecting Genetic and Environmental Determinants of Plasma Molecular Signatures and Their Link to Type 2 Diabetes Risk.

Magdalena Sevilla-González, Ningyuan Wang, Paul A Hanson, Allison Bebo, Daniel Hitchcock, Sarah Hsu, Kenneth E Westerman, Sara J Cromer, Valene Garr Barry, Yonah Borns-Weil and 16 more

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Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

26 authors.

Magdalena Sevilla-GonzálezClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.
Ningyuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Paul A HansonClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.
Allison BeboClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.
Daniel HitchcockMetabolomics Platform. The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Sarah HsuPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Kenneth E WestermanClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.ORCID 0000-0001-7619-1868
Sara J CromerDepartment of Medicine, Harvard Medical School, Boston, MA, 02115, USA.ORCID 0000-0002-4924-2049
Valene Garr BarryCenter for Reproductive Health Sciences, Obstetrics & Gynecology, Washington University in St. Louis School of Medicine, Saint Louis, MO 63108.
Yonah Borns-WeilClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.
Yixin ZhangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Ori Ben-YossefPrograms in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Chirag J PatelDepartment of Biomedical Informatics. Harvard Medical School, Boston, MA, 02115, USA.ORCID 0000-0002-8756-8525
Nora FranceschiniDepartment of Epidemiology, University of North Carolina at Chapel Hill, 27516 NC.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Julian Ávila-PachecoMetabolomics Platform. The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Clary B ClishMetabolomics Platform. The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.ORCID 0000-0001-8259-9245
Robert E GertzenDivision of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.ORCID 0000-0002-7892-193X
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Department of Epidemiology, University of Washington, Seattle, 98195, WA, USA.
Stephen S RichDepartment of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Jerome I RotterCenter for Reproductive Health Sciences, Obstetrics & Gynecology, Washington University in St. Louis School of Medicine, Saint Louis, MO 63108.
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.ORCID 0000-0002-0703-0742
James B MeigsDepartment of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Alisa K ManningClinical and Translational Epidemiology Unit. Mongan Institute. Massachusetts General Hospital. Boston, MA, 02114, USA.

Funding

UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
WOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0M
Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ALAN R. SALTIEL · 2003 to 2026
$40.4M
Wake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
Task Area A Core Study Operations.Task Area A shall encompass annual follow-up of cohort members, clinical endpoints ascertainment, study coordination activities, maintenance of the database and biosp75N92020D00001 · NHLBI · UNIVERSITY OF WASHINGTON · PI MCCLELLAND, ROBYN LEAGH · 2020 to 2025
$17.2M
Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
CHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
WOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC): TASK AREA A AND A275N92021D00002 · NHLBI · STATE UNIVERSITY OF NEW YORK AT BUFFALO · PI WACTAWSKI-WENDE, JEAN · 2021 to 2025
$6.9M
WOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC) - TO EXERCISE OPTION PERIOD ONE (1) AND REVISE CONTRACT ARTICLES.75N92021D00004 · NHLBI · STANFORD UNIVERSITY · PI STEFANICK, MARCIA · 2021 to 2025
$6.5M
NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS U01 HL120393NIDDK NIH HHS K99 DK139461NIDDK NIH HHS P30 DK063491NIDDK NIH HHS UM1 DK078616NIH HHS 75N98025D00022NIH HHS 75N98025D00024NIH HHS 75N98025D00025NIH HHS 75N98025D00026NIH HHS 75N98025D00027NIH HHS 75N98025D00028WHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
6 · The paper itself

Abstract

Background: Type 2 diabetes (T2D) is a heterogeneous disease shaped by both genetic, environmental, cultural, and socioeconomic factors, with well-documented disparities in incidence across populations. The molecular pathways underlying these disparities, however, remain poorly understood. Plasma metabolites and proteins integrate both genetic and environmental influences on type 2 diabetes (T2D) risk, providing insight into disease mechanisms. We aimed to quantify the variance in these molecular profiles explained by environmental and genetic ancestry domains and to apply causal inference approaches to identify environmentally and genetic ancestry influenced pathways contributing to T2D risk. Methods: We analyzed plasma proteomic and metabolomic profiles from 3,360 MESA participants (51.6% female), and in 1,333 participants from the Women's Health Initiative. To characterize the sources of variance in plasma proteomic and metabolomic profiles, we performed variance decomposition partitioning into four domains: biological (age, sex, BMI), genetic ancestry (principal components), lifestyle (smoking, alcohol intake, diet), and social determinants (self-reported race and ethnicity, income, education). To assess causal pathways towards T2D risk, we applied two-sample Mendelian Randomization to disentangle environmental and genetic contributors to T2D risk. Results: The largest share of variance in proteomic and metabolomic profiles was explained by biological and lifestyle factors, while race and ethnicity and genetic ancestry accounted for smaller but non-redundant contributions. Genetic ancestry was primarily associated with lipid and apolipoprotein variation, whereas race and ethnicity and socioeconomic factors were associated with immune and inflammatory signatures. Environmentally influenced metabolites (e.g., diacylglycerols, phosphatidylethanolamines, lysophosphatidylcholines) and vascular-inflammatory proteins were consistently linked to higher T2D risk, while genetic ancestry influenced triglycerides and IGFBP3 reflected inherited risk pathways. Mediation analyses showed that selected lipids and proteins (e.g., IGFBP2, HGF, SSC4D) explained 10-25% of racial/ethnic disparities in T2D. Mendelian randomization identified causal roles for seven lipid species and IGFBP3 in T2D risk. Conclusions: Our results reveal both genetic and non-genetic sources of variation in proteomic and metabolomic profiles, uncovering environmental and genetic pathways contributing to T2D risk. These findings advance precision medicine by identifying modifiable molecular mediators of disparities and potential causal targets for prevention.

Indexed as

BiomarkersDiabetes MellitusMetabolomicsPopulation GroupsPrecision MedicineProteomicsType 2

Identifiers

PMID41358287
PMCPMC12676399

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.