Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

Background: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. Methods: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of four population-based studies, comprising a total of 3,019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization (MR), using cis-protein quantitative loci genetic instruments identified from genome-wide association studies (GWAS) in over 30,000 individuals. To improve the precision of causal estimates, we implemented an MR model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and MR models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait MR analysis. Results: 44/90 proteins were positively associated with risk of incident HF (P < 6.0 x 10-4). Among these, eight proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23) and MMP-12 (Matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. Conclusions: We identified 44 circulating proteins that were associated with incident HF, of which eight showed evidence of a causal relationship and seven were druggable, including adrenomedullin which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases

Genetic risk and incident venous thromboembolism in middle-aged and older adults following COVID-19 vaccination

Background COVID-19 vaccination has been associated with increased venous thromboembolism (VTE) risk. However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination. Methods Using data from the UK Biobank, which contains in-depth genotyping and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants. We prospectively assessed associations between PRS and incident VTE immediately after first- and the second-dose vaccination and among historical unvaccinated cohorts during the pre- and early pandemic. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models. Results Of 359 310 individuals receiving one dose of a COVID-19 vaccine, 160 327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days' follow-up, 88 and 299 individuals developed VTE, respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70-1.08) and 0.92 (0.82-1.04) per 100 000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (1.15-1.73) in 28 days and 1.36 (1.22-1.52) in 90 days). Similar associations were found in the historical unvaccinated cohorts. Conclusions The strength of genetic susceptibility with post-COVID-19-vaccination VTE is similar to that seen in historical data. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines. These findings suggest that, at the population level, the VTE that occurred after the COVID-19 vaccination has a similar genetic etiology to the conventional VTE