Mendelian randomization of circulating proteome identifies actionable targets in heart failure.

BACKGROUND: Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown. RESULTS: We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates. CONCLUSIONS: Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF.

Calcific aortic valve disease: mechanisms, prevention and treatment.

Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. Age and congenital bicuspid aortic valve morphology are important and unalterable risk factors for CAVD, whereas additional risk is conferred by elevated blood pressure and plasma lipoprotein(a) levels and the presence of obesity and diabetes mellitus, which are modifiable factors. Genetic and molecular studies have identified that the NOTCH, WNT-ß-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD. Although no medical therapy is effective for reducing or preventing the progression of CAVD, studies have started to identify actionable targets.

Connectome and regulatory hubs of CAGE highly active enhancers.

Evidence indicates that enhancers are transcriptionally active. Herein, we investigated transcriptionally active enhancers by using cap analysis of gene expression (CAGE) combined with epigenetic marks and chromatin interactions. We identified CAGE-tag highly active (CHA) enhancers as distant regulatory elements with CAGE-tag ≥ 90th percentile and overlapping with H3K27ac peaks (4.5% of enhancers). CHA enhancers were conserved between mouse and man and were independent from super-enhancers in predicting cell identity with lower P-values. CHA enhancers had increased open chromatin and a higher recruitment of cell-specific transcription factors as well as molecules involved in 3D genome interactions. HiChIP analysis of enhancer-promoter looping indicated that CHA enhancers had a higher density of anchor loops when compared to regular enhancers. A subset of CHA enhancers and promoters characterized by a high density of chromatin loops and forming hub regulatory units were connected to the promoter of immediate early response genes, genes involved in cancer and encoding for transcription factors. Promoter of genes within hub CHA regulatory units were less likely to be paused. CHA enhancers were enriched in gene variants associated with autoimmune disorders and had looping with causal candidate genes as revealed by Mendelian randomization. Hence, CHA enhancers form a dense hierarchical network of chromatin interactions between regulatory elements and genes involved in cell identity and disorders.