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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research is based on data from the Million Veteran Program at the Office of Research and Development at the Veterans Health Administration and this work was supported by awards #MVP037 [BLR&D Merit Award BX005831] and Veterans Affairs Grant I01CX001922 (PI: Joseph) and #MVP001 [I01-BX004821]. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. We also acknowledge the VA Merit Grant I01-CX001025 (PI: Wilson/Cho). The British Heart Foundation funded the manual analysis to create a cardiovascular magnetic resonance imaging reference standard for the UK Biobank imaging resource in 5000 CMR scans (www.bnf.org.uk; PG/14/89/31194). This work acknowledges the support of the National Institute for Health and Care Research Barts Health NHS Trust, Queen Mary University of London, St George's University Hospitals NHS Foundation Trust and St George's University of London. This article is supported by the London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare (AI4VBH), which is funded from the Data to Early Diagnosis and Precision Medicine strand of the government's Industrial Strategy Challenge Fund, managed and delivered by Innovate UK on behalf of UK Research and Innovation (UKRI). Views expressed are those of the authors and not necessarily those of the AI4VBH Consortium members, the NHS, Innovate UK, or UKRI. This work was funded by UKRI Programme Grant MC\_UU\_00002/18. SEP acknowledges support from the "SmartHeart" EPSRC programme grant (www.nihr.ac.uk; EP/P001009/1). NA acknowledges support from Medical Research Council for his Clinician Scientist Fellowship (MR/X020924/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Veterans Affairs Central Institutional Review Board gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.