Large-scale proteomics identifies circulating markers of pulmonary pressure and pulmonary hypertension risk

Pulmonary hypertension, defined by elevated pressure in the pulmonary circulation, is morbid and diagnosing is challenging as no early-stage blood markers are currently available. Here we show that large-scale proteomic profiling across several independent observational cohorts identifies 22 proteins associated with echocardiography-derived pulmonary artery systolic pressure, several of which are independently associated with invasive measures of pulmonary vascular disease, structural remodeling of the pulmonary vasculature, and subsequent risk of pulmonary hypertension. Genetic analyses support a potential causal role for NOTCH3 and identify a common splice-regulating genetic variant that may modify susceptibility to pulmonary vascular stressors. Protein-based clustering further reveals two distinct biological subtypes associated with increased risk of pulmonary hypertension. Together, these findings identify candidate biomarkers of pulmonary hypertension, implicate pulmonary vascular remodeling in early-stage disease with a potential causal role for NOTCH3, and discover and validate two distinct endotypes of pulmonary hypertension risk in the community. By integrating proteomics, genetics and imaging, this study identifies candidate blood biomarkers of pulmonary hypertension, implicates NOTCH3 in disease development, and defines distinct biological subtypes of individuals at risk for this condition.