Modular PheWAS reveals the therapeutic heterogeneity landscape of Danghong injection on stable angina pectoris

Stable angina pectoris (SAP) is a common risk factor for myocardial infarction and death. The genomic, transcriptomic, and phenomic heterogeneities of SAP require combination therapies. Multi-target drugs with fixed doses are emerging as scalable and promising prevention and therapeutic strategies for SAP. However, the identification of targets and underlying mechanisms of multi-target drugs for optimal clinical efficacy remains insurmountable. Here, we report a modular phenome-wide association study (MoPheWAS) of Danhong Injection (DHI), a clinically proven effective anti-SAP drug. The interrelated multitargets of DHI were divided into 32 On-modules. Eleven clinical SAP phenotypes defined by the Seattle Angina Questionnaire and serum lipids were interactively associated with 14 DHI efficacy-related Phe-modules. The intrinsic polymorphic associations between SAP phenotypes and Phe-modules manifested systematic positive/negative regulation of specific one-to-one as well as complex many-to-many relationships. These Phe-modules were conserved, transformed, or newly emerged modules involving G-protein-coupled receptor signaling and kinase binding. In vitro RNAi analysis confirmed the hub genes GALR1/BCMO1 in Mod-29 as multiple targets for the anti-ischemic effect of DHI. The landscape of modular regulators and polymorphic phenomic associations revealed the multi-target mechanisms underlying the therapeutic heterogeneity of SAP. Therefore, MoPheWAS may provides a novel systematic paradigm for identifying multiple phenomic targets of complex polygenic diseases.