Divergent genetic mediator signatures of adiposity-related metabolic liabilities and coronary artery disease.
- 1Centro de Investigacion Cientifica de Yucatan
Abstract
BackgroundObesity and leanness lie at opposite ends of the weight spectrum, yet both carry coronary risk when metabolically dysfunctional. A 2025 Commission redefined obesity around organ function rather than body mass, but whether that distinction reflects a difference in causal architecture, and whether the two high-risk phenotypes reach disease by distinct routes, is untested.
MethodsWe conducted two-sample Mendelian randomization of the four combinations of adiposity and metabolic health against coronary artery disease (CARDIoGRAMplusC4D; 60,801 cases), using published adiposity and insulin-resistance instruments. Thirty mediators were interrogated identically in every quadrant by two-step Mendelian randomization with multivariable adjustment, and the pipeline replicated with an independent instrument sharing five of fifty-three variants.
ResultsAdiposity with preserved metabolic function was protective (odds ratio 0.28, 95% CI 0.19-0.42), whereas adiposity with metabolic dysfunction (1.90, 1.42-2.55) and leanness with metabolic dysfunction (1.86, 1.52-2.27) conferred indistinguishable risk (ratio of odds ratios 1.02; P = 0.91). The unhealthy obese phenotype acted through triglycerides and diabetes; the unhealthy lean through apolipoprotein B, blood pressure and diabetes, sharing no other conduit. High-density lipoprotein cholesterol and triglycerides collapsed despite being the most strongly instrumented exposures, indicating causal redundancy rather than weak-instrument bias.
ConclusionsCoronary risk follows the failure of adipose storage capacity, not its magnitude. The two high-risk phenotypes reach the same endpoint by divergent causal architectures that reproduce in full with an independent instrument, and the metabolically unhealthy lean phenotype carries risk equal to clinical obesity while falling outside a framework that requires excess adiposity to be confirmed first.
What Is New?O_LIAdiposity with preserved metabolic function lowers coronary risk (odds ratio 0.28), whereas adiposity with metabolic dysfunction raises it (1.90); the distinction between preclinical and clinical obesity therefore reflects a difference in causal direction, not a threshold along fat mass. C_LIO_LILeanness with metabolic dysfunction carries risk indistinguishable from that of unhealthy obesity (1.86; P = 0.91 for the difference), yet falls outside a diagnostic framework that requires excess adiposity to be confirmed before organ function is assessed. C_LIO_LIThe two high-risk phenotypes reach coronary disease by divergent routes -- triglycerides and diabetes in the obese, apolipoprotein B, blood pressure and diabetes in the lean -- converging only on diabetes. C_LI
What Are the Clinical Implications?O_LIThe lean patient at coronary risk is not identified by body mass index or by the standard lipid panel; apolipoprotein B and blood pressure are the measures that detect this phenotype. C_LIO_LIBecause the causal levers differ between phenotypes, a single risk-mitigation strategy cannot serve both: triglyceride and glycaemic control in the obese phenotype, apolipoprotein B lowering and blood pressure management in the lean. C_LIO_LIFunctional assessment of cardiometabolic risk should not be gated behind an anthropometric threshold, since storage failure can occur at any body size. C_LI
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BibTeX
@misc{campos2026divergent,
title = {{Divergent genetic mediator signatures of adiposity-related metabolic liabilities and coronary artery disease.}},
author = {J. A. SIMON CAMPOS and H. Laviada-Molina and P. CAMPOS CORZO and E. CASTANO DE LA SERNA},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.26362109},
url = {https://www.medrxiv.org/content/10.64898/2026.09.02.26362109v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Divergent genetic mediator signatures of adiposity-related metabolic liabilities and coronary artery disease.
AU - J. A. SIMON CAMPOS
AU - H. Laviada-Molina
AU - P. CAMPOS CORZO
AU - E. CASTANO DE LA SERNA
PY - 2026
DA - 2026/09/02
PB - medRxiv
DO - 10.64898/2026.09.02.26362109
UR - https://www.medrxiv.org/content/10.64898/2026.09.02.26362109v1
AB - BackgroundObesity and leanness lie at opposite ends of the weight spectrum, yet both carry coronary risk when metabolically dysfunctional. A 2025 Commission redefined obesity around organ function rather than body mass, but whether that distinction reflects a difference in causal architecture, and whether the two high-risk phenotypes reach disease by distinct routes, is untested. MethodsWe conducted two-sample Mendelian randomization of the four combinations of adiposity and metabolic health against coronary artery disease (CARDIoGRAMplusC4D; 60,801 cases), using published adiposity and insulin-resistance instruments. Thirty mediators were interrogated identically in every quadrant by two-step Mendelian randomization with multivariable adjustment, and the pipeline replicated with an independent instrument sharing five of fifty-three variants. ResultsAdiposity with preserved metabolic function was protective (odds ratio 0.28, 95% CI 0.19-0.42), whereas adiposity with metabolic dysfunction (1.90, 1.42-2.55) and leanness with metabolic dysfunction (1.86, 1.52-2.27) conferred indistinguishable risk (ratio of odds ratios 1.02; P = 0.91). The unhealthy obese phenotype acted through triglycerides and diabetes; the unhealthy lean through apolipoprotein B, blood pressure and diabetes, sharing no other conduit. High-density lipoprotein cholesterol and triglycerides collapsed despite being the most strongly instrumented exposures, indicating causal redundancy rather than weak-instrument bias. ConclusionsCoronary risk follows the failure of adipose storage capacity, not its magnitude. The two high-risk phenotypes reach the same endpoint by divergent causal architectures that reproduce in full with an independent instrument, and the metabolically unhealthy lean phenotype carries risk equal to clinical obesity while falling outside a framework that requires excess adiposity to be confirmed first. What Is New?O_LIAdiposity with preserved metabolic function lowers coronary risk (odds ratio 0.28), whereas adiposity with metabolic dysfunction raises it (1.90); the distinction between preclinical and clinical obesity therefore reflects a difference in causal direction, not a threshold along fat mass. C_LIO_LILeanness with metabolic dysfunction carries risk indistinguishable from that of unhealthy obesity (1.86; P = 0.91 for the difference), yet falls outside a diagnostic framework that requires excess adiposity to be confirmed before organ function is assessed. C_LIO_LIThe two high-risk phenotypes reach coronary disease by divergent routes -- triglycerides and diabetes in the obese, apolipoprotein B, blood pressure and diabetes in the lean -- converging only on diabetes. C_LI What Are the Clinical Implications?O_LIThe lean patient at coronary risk is not identified by body mass index or by the standard lipid panel; apolipoprotein B and blood pressure are the measures that detect this phenotype. C_LIO_LIBecause the causal levers differ between phenotypes, a single risk-mitigation strategy cannot serve both: triglyceride and glycaemic control in the obese phenotype, apolipoprotein B lowering and blood pressure management in the lean. C_LIO_LIFunctional assessment of cardiometabolic risk should not be gated behind an anthropometric threshold, since storage failure can occur at any body size. C_LI
ER -