Mechanistic endotyping of the ROS/cGMP disease cluster in the Estonian Biobank

We hardly comprehend any disease mechanistically, meaning most disease definitions are organ- and symptom-based and fail to represent the underlying mechanism of the disease. Current therapies can thus only treat symptoms chronically yielding unprecise and low patient-relevant outcomes ( 1, 2). Symptom-based disease definitions also have the risk of agglutinating different molecular mechanisms that cause similar symptoms under umbrella disease terms. As a result, they are combined into a single common and complex disease entity that is impossible to untangle with present diagnostic methods. Contrarily, apparently unrelated disease phenotypes co-occur in the same patient beyond chance, which may indicate shared causal mechanisms ( 3). Thus, in order to reach precision medicine and to achieve treatment accuracy, we must first determine the underlying disease mechanism and endotype patients based on the cause of the disease. This approach will redefine diseases, shifting the focus from symptoms and affected organs to the underlying mechanisms and causes ( 4). Here, we investigate one of the best studied diseasome clusters of fourteen heterogeneous cardiovascular, neuro-psychiatric, metabolic and pulmonary comorbid disease phenotypes of unmet medical need, defined - at least in part - by reactive oxygen species ( ROS)-induced dysfunction of and cGMP signaling (ROCG) ( 5, 6). Previously, we have shown that NADPH oxidase 5 (NOX5) levels in endothelial microparticles were able to identify the ROCG endotype in hypertensive patients ( 7). Here, we used a high-throughput screening plasma antibody assay to measure NOX5 plasma levels and analyze over 1,000 human samples of the ROCG cluster in collaboration with the Estonian biobank to identify the prevalence of the ROCG endotype. Stratifying patients according to both phenotype and endotype will allow for high precision, i.e., low number needed to treat therapeutic interventions. These data show that even for supposedly complex diseases, endotyping for precision medicine and mechanistic disease re-definition is possible.