An integrative model of cardiometabolic traits identifies two types of metabolic syndrome

Human diseases arise in a complex ecosystem composed of disease mechanisms and the whole-body state. However, the precise nature of the whole-body state and its relations with disease remain obscure. Here we map similarities among clinical parameters in normal physiological settings, including a large collection of metabolic, hemodynamic and immune parameters, and then use the mapping to dissect phenotypic states. We find that the whole-body state is faithfully represented by a quantitative two-dimensional model. One component of the whole-body state represents ‘metabolic syndrome’ (MetS) – a conventional way to determine the cardiometabolic state. The second component is decoupled from the classical MetS, suggesting a novel “non-classical MetS” that is characterized by dozens of parameters, including dysregulated lipoprotein parameters (e.g. high LDL-cholesterol and low free cholesterol in small HDL particles) and attenuated cytokine responses of PBMCs to ex vivo stimulations. Both components are associated with disease, but differ in their particular associations, thus opening new avenues for improved personalized diagnosis and treatment. These results provide a practical paradigm to describe whole-body states and to dissect complex disease within the ecosystem of the human body.