Divergent causal signatures of the adiposity quadrants on coronary artery disease

Background

Obesity 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.

Methods

We 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.

Results

Adiposity 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.

Conclusions

Coronary 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?

• Adiposity 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.

• Leanness 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.

• The 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.

What Are the Clinical Implications?

• The 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.

• Because 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.

• Functional assessment of cardiometabolic risk should not be gated behind an anthropometric threshold, since storage failure can occur at any body size.