Large-scale Mendelian randomization identifies novel pathways as therapeutic targets for heart failure with reduced ejection fraction and with preserved ejection fraction

We used expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to conduct genome-wide Mendelian randomization (MR) using 27,799 cases of heart failure (HF) with reduced ejection fraction (HFrEF), 27,579 cases of HF with preserved ejection fraction (HFpEF), and 367,267 control individuals from the Million Veteran Program (MVP). We identified 70 HFrEF and 10 HFpEF gene-hits, of which 58 are novel. In 14 known loci for unclassified HF, we identified HFrEF as the subtype responsible for the signal. HFrEF hits ZBTB17, MTSS1, PDLIM5, and MLIP and novel HFpEF hits NFATC2IP, and PABPC4 showed robustness to MR assumptions, support from orthogonal sources, compelling evidence on mechanism of action needed for therapeutic efficacy, and no evidence of an unacceptable safety profile. We strengthen the value of pathways such as ubiquitin-proteasome system, small ubiquitin-related modifier pathway, inflammation, and mitochondrial metabolism as potential therapeutic targets for HF management. We identified IL6R, ADM, and EDNRA as suggestive hits for HFrEF and LPA for HFrEF and HFpEF, which enhances the odds of success for existing cardiovascular investigational drugs targeting. These findings confirm the unique value of human genetic studies in HFrEF and HFpEF for discovery of novel targets and generation of therapeutic target profiles needed to initiate new validation programs in HFrEF and HFpEF preclinical models.